Essential Oils with Pharmacological Properties

### **Chapter 6**

## Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant Activity and Inhibition of Cholinesterase Enzymes

*Mejra Bektašević and Olivera Politeo*

#### **Abstract**

This chapter will be described oxidative stress related to modern age illness as well as biological activity of essential oils and essential oil components in terms of their antioxidant activity. The importance of essential oils and their constituents in terms of protecting lipids and proteins from oxidation will also be explained. Alzheimer's disease as a disease related to oxidative stress and strategies in their treatment by using essential oil components as cholinesterase inhibitors will also be described. As case studies will be pointed out medicinal plants, endemic *Saturejasubspicata* L., and widely used *Menthapulegium* L. growing in Bosnia and Herzegovina.

**Keywords:** oxidative stress, essential oils, biological activity, antioxidants, Alzheimer's disease, cholinesterase inhibitors, *Saturejasubspicata*, *Menthapulegium*

#### **1. Introduction**

Under normal physiological conditions, the production of harmful reactive species caused by oxidative processes and antioxidant defense are in balance. If the reactive oxygen species and other species production exceed the antioxidant capacity of a living system, reactive oxygen and nitrogen species (ROS and RNS) may react with macromolecules, causing structural and/or functional damage to cellular enzymes and genetic material. An excess of reactive species and damage caused by their action is called oxidative stress.

In a state of oxidative stress, an excess of ROS and RNS may damage lipids, proteins, carbohydrates, and nucleic acids. Free radicals attack unsaturated fatty acids in biological membranes causing lipid peroxidation. Lipid peroxidation is an enzymatic reaction catalyzed by the enzyme lipoxygenase [1]. This enzyme is found in the erythrocytes and leukocytes of animals, as well as in many plant organisms. Its substrate is linoleic and linolenic acid in plants, and arachidonic acid in animals, while oleic acid is not oxidized. Lipid peroxidation results in decreased membrane fluidity, loss of

enzymes and receptor activity, damage to membrane proteins and other macromolecules, which leads to apoptosis [2].

Oxidative modification of proteins, reversible and irreversible, occurs during redox signaling and other cellular processes. It also occurs as a result of oxidative stress. Exposure of proteins to hydroxyl OH• and/or superoxide radicals O2 •− leads to their structural modifications. Modified proteins may further undergo spontaneous fragmentation and cross-linking or show a significant increase in proteolysis. An oxidative attack of a polypeptide backbone is usually initiated by hydroxyl OH• . By an experimental generation of radicals, using water radiolysis or decomposing hydrogen peroxide H2O2 in a metal-catalyzed reaction - and in the interaction with lipids - alkyl, alkoxy, and alkylperoxyl radical intermediates can be formed, which affect peptide bond cleavage in several ways.

Tryptophan, histidine, and cysteine are the most sensitive to reactive oxygen species. In addition to fragmentation, oxidation of the amino acid residues of lysine, arginine, proline, and threonine increases carbonyl concentration, so the presence of carbonyl groups can be used as an indicator of protein oxidation.

Oxidative modification of proteins also occurs in reaction with aldehydes, which are formed during lipid peroxidation process. End products of lipid peroxidation, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), as well as oxidation products of polyunsaturated fatty acids cause oxidative damage to proteins [3].

Oxidative modification of proteins is present in diseases and changes associated with the aging process, such as atherosclerosis, tumors, neurodegenerative diseases, and aging. Protein carbonylation occurs with a large number of modifications and is a marker of oxidative stress. During the first two-thirds of life, the level of protein carbonylation slowly increases, while its level rises sharply in the last third. Protein carbonylation negatively affects the functions of proteins themselves, which suggests that this modification may be one of the causes of the aforementioned undesirable processes [4].

#### **2. Oxidation and food**

Apart from the living organisms, the oxidation process occupies an important place in the food, pharmaceutical, and cosmetic industries. It includes the oxidation of protein molecules, vitamins, but above all, the oxidation of lipid molecules [5].

Oxidation of lipid molecules is a major problem in the food industry, as it leads to changes in the organoleptic properties of food, a decrease in its nutritional value, as well as the formation of radical components that can endanger consumers' health.

Lipid oxidation in food implies a whole range of chemical changes that result from the reaction of lipids with oxygen. Triacylglycerols and phospholipids are hardly volatile molecules and do not directly affect the aroma of the product. During lipids oxidation from fatty acids, volatile compounds have formed that lead to an undesirable aroma of products known as rancidity [6].

Polyunsaturated fatty acids oxidize much faster than monounsaturated or saturated ones. The rate of lipid oxidation is influenced by the number and position of double bonds [1]. The methylene group (-CH2-) located between the two double bonds is very susceptible to oxidation. Linoleic acid is subject to oxidation, as it has a methylene group between two double bonds, at position 11. Its oxidation produces two hydroperoxides. The main secondary product of linoleic acid autooxidation is hexanal. Lipid autooxidation is an autocatalytic reaction, which means that it progresses over time due to the formation of products that catalyze the reaction themselves.

*Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant… DOI: http://dx.doi.org/10.5772/intechopen.102874*

**Figure 1.** *The lipid oxidation phases [7].*

Lipid peroxidation includes three phases: initiation, propagation, and termination (**Figure 1**). From the peroxides formed at the beginning, secondary oxidation products are formed: aldehydes, ketones, epoxides, and other compounds, which also have negative biological effects, such as loss of essential amino acids and lipid-soluble vitamins [7].

In the first phase, oxygen from the air attacks unsaturated fatty acids (LH), creating free radicals of fatty acids (peroxy LO2 • , alkoxyl LO• , or alkyl radicals L• ). In the second phase of the reaction, hydroperoxides (LOOH) and free peroxide radicals (LOO• ) are formed from free radicals by binding oxygen to free fatty acid radicals.

Hydroperoxides (primary oxidation products) are labile, so they are further decomposed into free radicals and decomposed oxidation products. These degradation products of oxidation (secondary oxidation products) are carbonyl compounds (aldehydes and ketones), fatty acids, alcohols, epoxides, etc., some of which give off an unpleasant, rancid odor characteristic of oxidized fat.

Lipid autooxidation is often initiated by free radicals from an unknown source. It is accelerated by rising temperatures, light and the presence of trace metals. Reductive forms of transition metals are more efficient in the hydrogen peroxide decomposition, so reductive components such as superoxide anion (O2 •−) and ascorbic acid further promote lipid oxidation. Redox cycling of iron in the presence of superoxide anions in lipid oxidation is known as the Haber-Weiss reaction, while the second step of this reaction is known as the Fenton reaction:

$$\text{Fe}^{2+} \star \text{H}\_{2}\text{O}, \rightarrow \text{Fe}^{3+} \star \text{OH}^{\bullet} \text{ + } \text{OH}^{-}.$$

The resulting hydroxyl radicals (OH• ) are the most reactive ROS species.

Ascorbic acid can also participate in the Haber-Weiss type reaction, but unlike superoxide anions, ascorbic acid may also act as an antioxidant at higher concentrations.

The control of the level of free radicals, prooxidants, and oxidation intermediates is used to protect the lipid components of food from oxidation. Free radical scavengers (FRS) inhibit lipid oxidation by reacting faster than unsaturated fatty acids with free radicals. They can react with peroxyl(LOO• ) or alkoxyl(LO• ) radicals in the following reaction:

Phenolic components are known to be good free radicals scavengers, as they donate a hydrogen atom, and the resulting radical has low energy due to its delocalization in the structure of phenol ring (**Figure 2**) [6].

**Figure 2.** *Delocalization of phenol radical [6].*

The most commonly used synthetic antioxidants are substituted monophenolic compounds, such as 2,6-di-*tert*-butyl-4-hydroxytoluene (BHT), 2-*tert*-butyl-4-hydroxyanisole and 3-*tert*-butyl-4-hydroxyanisole (2- and 3-BHA), propyl gallate(PG) and *tert*-butyl hydroquinone (TBHQ ). The addition of the antioxidant BHA prolongs the stability time of lipid-based foods (e.g., butter, fat, meat, dairy, vegetable oils) by a few months to a few years. BHT is less effective than BHA because two tertiary butyl groups sterically affect the radical reaction. PG is poorly soluble in water. It is less commonly used in the food industry because it binds Fe3+ ions and reduces them to their Fe2+ form. When this antioxidant is used in food, it must be combined with chelating agents (such as citrate) to prevent this phenomenon. TBHQ is one of the best antioxidants added to oil intended for frying. Unlike PG, it does not complex with iron and copper ions. According to European rules, the permitted amount of BHT, BHA, and PG in food is 100 μg/g of lipids [8]. BHA and BHT are very effective in their role, but are easily volatile and thermolabile, which makes their use limited [9]. Some studies have shown that the use of some antioxidants of synthetic origin has negative effects on human health due to the promotion of carcinogenesis [10, 11].

For these reasons, there is a tendency to replace synthetic antioxidants, where possible, with non-toxic antioxidants of natural origin. More recently, essential oils have also been used as a substitute for synthetic antioxidants, in those food canning sectors where their use does not adversely affect product flavor [12].

#### **3. Antioxidant activity of essential oil components**

In addition to oxidative damage and death of cells, tissue damage and various pathological conditions may be the consequence of oxidative stress. Numerous forms of malignant disease are thought to be the result of oxidative DNA damage and the resulting mutations. The negative impact of free radicals is believed to lead to various autoimmune diseases, diabetes, rheumatic diseases, cardiovascular disease and heart attack, kidney disease, infectious diseases, neurodegenerative diseases

#### *Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant… DOI: http://dx.doi.org/10.5772/intechopen.102874*

(Alzheimer's disease), etc. The aging process itself is described as the process of accumulation of numerous oxidative damage accumulated over time.

Given that the oxidative stress is associated with the etiology and pathogenesis of many diseases, it is believed that eliminating the causes of oxidative stress may prevent or delay the occurrence of pathological changes and reduce the occurrence of diseases. Numerous studies show that regular intake of fruits, vegetables, grains, and beverages have a positive effect on diseases that are mediated by the activity of free radicals. Therefore, natural antioxidants – alone or in the form of extracts – may be useful in the treatment of such diseases. Thus, the reason for the great interest in researching the antioxidant activity of aromatic, medicinal, and edible plants [13].

In situations of disturbed homeostasis, as well as in the prevention of disease development, the intake of antioxidants in food may be of great importance. In this regard, essential oils, plant extracts, or their individual components with good antioxidant activity may be used. From a chemical point of view, essential oils are complex mixtures of a large number of compounds, which makes their activity difficult to test.

With the exception of some phenolic components, whose antimicrobial and antioxidant activity is well known, such data are not available for most other components of essential oils. Numerous papers on essential oils mention synergism, antagonism, additivity, but such claims are rarely accompanied by experimental confirmation [12].

A study by Ruberto and Baratta [12] examined the antioxidant activity of 100 pure compounds, common constituents of essential oils, using two methods. Of the thirteen non-oxygenated monoterpenes, terpinolene, α-terpinene, γ-terpinene, and sabinen showed very high activity. The activity of α-terpinene and γ-terpinene was similar to that shown by α-tocopherol. An active methylene group is thought to contribute to this activity of the aforementioned compounds. Of the 34 oxygenated monoterpenes tested, thymol and carvacrol showed activity as did α-tocopherol. It is known that thymol and carvacrol contribute the most to the antioxidant activity of essential oils that contain them. Alcohols were the most active in this class of compounds, with the exception of linalool, which showed prooxidative activity. Ketones showed lower activity. Non-oxygenated sesquiterpenes were not active, while oxygenated sesquiterpenes showed activity similar to that of oxygenated monoterpenes. Germacron, a cyclic ketone, showed slightly more pronounced activity, while nerolidol showed prooxidative activity. Phenols, benzene derivatives, have shown the best results. They are more effective in preventing the formation of primary oxidation products, as opposed to preventing the formation of secondary oxidation products. Non-terpene compounds, which are present in essential compounds in a smaller amount, showed weak antioxidant activity – just like non-oxygenated sesquiterpenes [12].

More recently, essential oils have also been used as a substitute for synthetic antioxidants, in those food preservation sectors where their use does not adversely affect product flavor [12].

Due to their specific chemical structure, plant phenolic compounds may act as strong antioxidants, due to their ability to interrupt chain reactions by donating hydrogen atom or electron to a free radical, while taking on a stable non-reactive conformation. However, their activity depends on a number of factors: degree of hydroxylation, polarity, solubility, reducing potential, stability of the resulting radical, etc. Hydroxycinnamic acids, the components of essential oils, show stronger activity compared to hydroxybenzoic acids because they donate hydrogen atoms more easily [14]. Polyphenols are proven to have a positive effect on cognitive abilities and neurodegenerative changes caused by aging [15].

Currently, there is a disparity in knowledge about the *in vivo* and *in vitro* effects of polyphenols as antioxidants [16]. Due to the lack of knowledge regarding the safety of higher doses intake, it is believed that the level of polyphenols, which are entered into the human body, should not exceed that in which they are otherwise found in food [17].

#### **4. Neurotransmitter acetylcholine and cholinesterase inhibitors**

The neurotransmitter acetylcholine (ACh) is present in the nervous system, where it enables cerebral-cortical activity and development, control of cerebral blood flow, control of sleep–wake cycles, as well as learning and memory processes (**Figure 3**). The enzyme cholineacetyltransferase (ChAT) catalyzes the production of acetylcholine (ACh) in cholinergic neurons, from choline and acetyl coenzyme A.

Releasing acetylcholine from the synaptic vesicle of the presynaptic membrane into the synaptic cleft, it binds to cholinergic receptors (nicotinic and muscarinic receptors) on the postsynaptic membrane of the cholinergic synapse or on muscle cells. This triggers a series of processes that result in membrane depolarization and further signal transmission [18].

ACh hydrolysis controls the transmission of nerve impulses at the cholinergic synapses of the central and peripheral nervous systems. The degradation of acetylcholine in the synaptic cleft by acetylcholinesterase (AChE) establishes the polarization of the postsynaptic membrane and impulse transmission ceases.

Two types of ChE are currently known: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). AChE is also called "true cholinesterase", while BChE is also known as "pseudocholinesterase" because it hydrolyzes many choline esters and other non-choline esters (butyrylcholine, succinylcholine, acetylcholine, acetylsalicylic acid, cocaine, and heroin).

Inhibition of AChE prevents the hydrolysis of ACh, thus prolonging its activity in the transmission of nerve impulses. This concept is applied in the treatment of diseases characterized by low ACh levels and is also being studied in toxicology because of health conditions and deaths caused by increased cholinergic stimulation [19].

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the cause of dementia in the elderly population. It affects about 2% of the population in industrialized countries. AD is characterized by the formation of neuritic plaques; extracellular accumulations of fibrils and amyloid-β-peptides, as well as neurofibrillary tangles; intracellular accumulations of τ-protein, in regions of the brain responsible for learning, memory, and emotional behavior. These changes cause neuronal degeneration, loss of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), which is manifested in the loss of neurotransmitters and other neuromodulators, and

**Figure 3.** *Structural formula of neurotransmitter acetylcholine (ACh).* *Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant… DOI: http://dx.doi.org/10.5772/intechopen.102874*

the disabling of synaptic transmission [18]. Currently, the treatment of this disease is limited to the treatment of symptoms of the disease, for which cholinesterase inhibitors (ChE) are used.

ChE inhibitors may be reversible, those which are bound by noncovalent interactions, or irreversible, which covalently bind to the serine of the catalytic triad. Reversible inhibitors bind to the active site, peripheral site or both, and the inhibition occurs as a result of conformational changes of the enzyme, electrostatic interactions of the inhibitor and the cationic part of the substrate, and steric and/or electrostatic interferences with the substrate entry into the active enzyme center.

A feature of the structure of good cholinesterase inhibitors is the presence of a positive charge and/or aromatic or hydrophobic substituents that facilitate the entry and placement of inhibitors in the active site of the enzyme [18].

Synthetic AChE inhibitors such as physostigmine, tacrine, and donepezil cause side effects such as hepatotoxicity and gastrointestinal disorders. Irreversible inhibitors may cause serious consequences and even death, as is the case with sarin, a poison gas, so reversible inhibitors are preferred in this regard [20].

#### **4.1 Essential oil components as cholinesterase inhibitors**

Bioactive substances from fruits, vegetables, and medicinal plants play a major role in slowing down many pathogeneses and neurodegenerative disorders, such as Alzheimer's disease. In addition to alkaloids, food rich in phytochemicals contains terpenes and polyphenols, which can be good cholinesterase inhibitors, alone or in synergy with each other [20].

Donepezil, rivastigmine, and galantamine are currently used to treat AD symptoms, such as cognitive dysfunction and memory impairment [21]. The aforementioned galantamine is a reversible inhibitor of AChE, which has been used since 2007 in the treatment of mild to moderate AD. It shows good pharmacological and pharmacokinetic properties, as well as a small number of side effects [22]. The use of most of the ChE inhibitors tested so far has been accompanied by side effects such as fatigue, sleep disorders, cardiorespiratory, gastrointestinal disorders, and low bioavailability. This was an incentive for further research with the aim of finding new ChE inhibitors of natural origin, with greater efficiency and bioavailability, as well as with fewer side effects [23].

Essential oils contain a number of bioactive components; terpenes, terpenoids, phenylpropanoid and other compounds, so a large number of them have been tested in terms of their ability to inhibit ChE. The results showed that some of the tested oils have a good ability to inhibit ChE. Comparing the results of different studies, it was noticed that some essential oils of similar composition have different abilities to inhibit ChE. The differences in the mentioned results may be attributed to the synergistic or antagonistic effect between the individual components of the essential oil. To investigate these effects, a number of studies have been conducted to identify and isolate individual constituents of essential oils with a significant ability to inhibit ChE [24].

The majority of the data obtained thus far in the research pertains to the study of the ability of smaller individual components of essential oils to inhibit AChE, while a few pertain to the study of BChE inhibition. However, given the role of BChE inhibition in the treatment of AD in the later stages of the disease, the interest in testing BChE inhibition has increased [24]. In terms of ChE inhibition, IC50 values are impacted by the enzyme concentration, inhibitors, and substrates, as well as other experimental conditions, making it difficult to compare the results obtained by different studies. It is important to standardize the protocols used in testing AChE and BChE inhibitors, so as to be able to detect them [25].

When it comes to the studies of the ability to inhibit ChE, most of these refer to the study of monoterpenes [24]. Of monoterpenes, 1,8-cineole and α-pinene are the most effective in inhibiting AChE. In addition to these two, the ability to inhibit AChE is shown by δ-2-carene (2-carene), δ-3-carene (3-carene), and mirtenal [18, 24], as well as geraniol, α-caryophyllene, and limonene [21]. Carvone also showed good AChE inhibitory activity [19].

Monoterpene carvacrol and its isomer thymol showed significant AChE inhibitory activity, with carvacrol activity being ten times higher, which indicates the importance of the hydroxyl group position for AChE inhibitory activity [26].

Among the monoterpenes with the *p*-menthane skeleton, pulegone was the most successful in terms of AChE inhibition [19]. Monoterpene camphor, bornyl acetate, carvone, β-pinene, fenchol, and fenchone show poorer ability to inhibit AChE [19].

Some studies show the existence of a synergistic effect of monoterpenes, especially between 1,8-cineole and α-pinene [19]. A synergistic effect is also present between the enantiomers of α-pinene and β-pinene (α-*S*-pinene: β-*S*-pinene, and α-*R*-pinene: β-*S*-pinene) in the mixture, at a ratio of 3:2 [27].

One of the ways in which terpenes inhibit AChE is through a hydrophobic ligand. The hydrophobic active site of AChE is the site where hydrophobic interactions take place, and terpene compounds, built from the skeletons of carbon and hydrogen atoms, thus contribute to the inhibition of cholinesterases [21].

Due to the differences in terpene compounds structure, it is difficult to determine the relationship between their structure and activity. When it comes to monoterpenes with a *p*-menthane skeleton, it has been established that ketone monoterpenes are better AChE inhibitors than the corresponding hydrocarbons and alcohols [19]. In the case of bicyclic monoterpenes, bicyclic hydrocarbons have a greater ability of inhibition than bicyclic alcohols and ketones. The position of the double bond increases the ability of inhibition, so 3-carene has a greater ability of inhibition than 2-carene [28].

Monoterpenes are much better inhibitors of AChE than BChE. Due to their low molecular weight, monoterpenes are more likely to inhibit ChE exerting steric or allosteric effects, whereby BChE does not affect the substrate's access to the enzyme site [18].

In a study examining 21 monoterpenes in terms of the ability to inhibit BChE, only 3carene showed BChE inhibiting ability (IC50 = 2000 μM) [29]. Monoterpenes α-pinene, 1,8-cineole, 1,8-cineole, linalool, terpinen-4-ol, linalyl acetate, thymol, γ-terpinene, and phenylpropanoid eugenol have shown good to moderate BChE inhibitory potential (IC50 = 0,1 to 1,0 mM) in various studies [24].

Of the flavonoids, flavones and isoflavones show the best activity, while xanthones and monoterpenes show weaker activity in the inhibition of cholinesterases (**Figure 4**) [18].

The most frequently studied sesquiterpenes for AChE inhibition are β-caryophyllene and α-humulene. In doing so, β-caryophyllene had a good ability to inhibit, in contrast to α-humulene (α-caryophyllene), which showed a weak ability to inhibit AChE [24]. In several studies, β-caryophyllene also showed good to moderate BChE inhibitory potential (IC50 = 0,1 to 1,0 mM) [24].

Diterpenes inhibit ChE at lower concentrations than monoterpenes, which indicates the importance of molecule size. Dihydrotanshinone and cryptotanshinone are non-competitive ChE inhibitors. Of triterpenes and steroids, ursolic acid, taraxerol, leucisterol, and oleanolic acid show ChE inhibitory activity [18].

*Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant… DOI: http://dx.doi.org/10.5772/intechopen.102874*

**Figure 4.**

*Some monoterpenes with cholinesterase inhibition activity.*

Given that BChE has a regulatory role in ACh hydrolysis, therapeutics that would inhibit both ChEs could exert additional positive effects in the treatment of AD, compared to inhibitors that inhibit only AChE. Thus, rivastigmine, which inhibits both ChEs, is very successful in the AD treatment. To date, there is no evidence that BChE inhibitors are more effective in reducing AD symptoms than AchE inhibitors [18].

In traditional medicine, many herbs are used in the treatment of cognitive disorders, including neurodegenerative diseases. The ethnopharmacological approach, testing of biological activity and isolation enabled the identification of potential AChE inhibitors of plant origin. Multifunctional compounds with several complementary biological functions are of particular interest. Plant extracts are the main sources of new compounds, AChE inhibitors [21]. In this regard, polyphenols are particularly interesting due to their positive effect on human health [20].

Many phytochemicals are bioactive compounds, some of which show ChE inhibitory activity and represent a model for the development of new drugs, ChE inhibitors. As terpenes and terpenoids have shown relatively weak inhibitory capacity in studies published so far, it is necessary to develop analogues with an improved efficiency [21].

Given the above, numerous plant extracts and essential oils, as well as their components, have been studied in terms of ChE inhibitory activity [18, 19, 20].

#### **5. The case study of** *Satureja subspicata* **and** *Mentha pulegium* **growing in Bosnia and Herzegovina**

*Satureja subspicata* (mountain savory) is a rare, endemic Dinaric species distributed in the eastern Mediterranean area [30]. *Satureja subspicata* (**Figure 5**) has long been utilized in Bosnia-Herzegovina's traditional medicine to treat leukemia and lymph node disorders. The herbal medicines of *Satureja subspicata* have been shown to be effective for a variety of cardiovascular diseases, especially arrhythmia, atrial fibrillation, and vascular diseases [31].

The essential oils obtained from various *Satureja* species have certain biological properties, such as antimicrobial [32, 33], antioxidant [33, 34], antiviral [35], antispasmodic and antidiarrheal [36, 37], anti-inflammatory and antinociceptive activities [38]. Carvacrol, thymol, β-caryophyllene, γ-terpinene, *p*-cymene, and linalool, all common compounds found in *Satureja* essential oil, have been shown to have strong antioxidant activity [39].

**Figure 5.** Satureja subspicata *L. (mountain savory).*

Thirty-four (34) volatile compounds (98.0% of the total oil) in *Satureja subspicata* essential oil from Bosnia-Herzegovina were identified using GC/MS and GC/ FID. The main classes of essential oil constituents were non-oxygenated monoterpenes (46.6%) and non-oxygenated sesquiterpenes (34.8%), followed by oxygenated monoterpenes (10.4%) and oxygenated sesquiterpenes (6.2%). The sesquiterpene ß-caryophyllene (14%) and non-oxygenated monoterpene *cis*-ß-ocimene (12.1%), as well as α-pinene (10.2%), were the main essential oil components. Other quantitatively important compounds were *trans*-ß-ocimene (8.8%), germacrene D (7.1%), caryophyllene oxide (6.2%), and myrtenol (6.1%) [40].

*Mentha pulegium* L. (pennyroyal) can be found in the area of Europe and Mediterranean [41]. In traditional medicine of Bosnia and Herzegovina, this plant is used for the treatment of nervous system disorders [31]. *Mentha pulegium* (**Figure 6**) stimulates digestive juices and helps with bloating and cramps. It is used for headaches and mild respiratory infections; it is a strong stimulant for the muscles of the uterus and can be used externally to relieve rheumatic problems, including gout [42].

Medicinal properties of *M. pulegium* are attributed to the monoterpenes present in the essential oil as well as polyphenol derivatives [43]. Essential oil of *M. pulegium* shows antifungal, insecticidal, antiparasitic, spasmolytic, and antioxidant properties [44]. Because of the mint-like odor, *M. pulegium* essential oil has a wide application; it is a constituent of foods and fragrances [45]. Pulegone, piperitone or piperitenone have been identified as dominant *M. pulegium* oil components [46]. Toxic effects of *M. pulegium* essential oil are mainly due to its main component pulegone. Reports suggest that the ingestion of up to 10 mL of *Mentha pulegium* oil causes gastritis and mild central nervous system toxicity without hepatorenal damage. The fatalities resulting from the ingestion of 15 to 30 mL of this oil [47]. Because of its potential toxicity pennyroyal is not recommended for children and other sensitive groups [45].

In *Mentha pulegium* essential oil growing in Bosnia and Herzegovina, 34 essential oil components (98% components of the oil), have been identified by GC/MS and

*Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant… DOI: http://dx.doi.org/10.5772/intechopen.102874*

**Figure 6.** Mentha pulegium *L. (pennyroyal).*

GC/FID. Monoterpenoids were the most represented group of compounds (90.4%), with pulegone (54.4%), *p*-menthone (14.0%), piperitenone (12.8%), piperitone (3.7%), and isopulegone (2.5%) being dominant. Monoterpenes accounted for a total of 3.3%. The most prevalent monoterpenes were: limonene (1.2%), α-pinene (0.9%), and ß-pinene (0.6%). Of sesquiterpenes (1.7%), germacrene D was the most prevalent (1.1%). The non-terpenic compounds accounted for 2.5%, with 3-octanol being the most prevalent (2.3%) [48].

The antioxidant capacity of the essential oils of *Satureja subspicata* and *Mentha pulegium* were evaluated by the commonly used DPPH and FRAP assay. In DPPH test, in comparison to reference antioxidants ascorbic acid (*IC*50 = 0.35 g/L) and hydroxyanisole (BHA) (*IC*50 = 0.37 g/L), essential oil of tested plants showed lower antioxidant potential for *Satureja subspicata* essential oil (*IC*50 = 3.3 g/L) [40] and good antioxidant potential for *Mentha pulegium* essential oil (IC50 = 94.3 μg/mL) [48].

The antioxidant potential of *S. subspicata* and *M. pulegium* essential oils, in concentration of 1 g/L tested by FRAP assay were for *S. subspicata* essential oil 73.89 (Eq Fe2+μM), [40] and for *M. pulegium* essential oil 6.71 (Eq Fe2+μM) [48]. Ascorbic acid and BHA had antioxidant potentials of 5568.43 and 5586.27 (Eq Fe2+μM) respectively, for the same tested concentration [40, 48].

Low quantities of phenol compounds or monoterpenoids (such as carvacrol and thymol), which are good antioxidant compounds, may explain low antioxidant activity of *S. subspicata* essential oil [49]. As pulegone and menthone are known for their antioxidant properties, [50] the obtained results for *M. pulegium* essential oil can be explained by the high content of pulegone (54.4%) and the significant content of *p*-menthone (14.0%). Good antioxidant activity is also shown by 1,8-cineole, [51] which was also identified as one of the components of the tested *M. pulegium* oil (0.2%) [48].

The ability of *Satureja subspicata* and *Mentha pulegium* essential oils to inhibit enzymes acetylcholinesterase and butyrylcholinesterase (AChE and BChE) was tested by Ellman's method. The essential oils were tested at initial concentrations of 1 and 2 mg/mL. At an initial concentration of 0.1 mg/mL, eserine - the well-known cholinesterase (ChE) inhibitor - inhibited AChE with 95.9%, while BChE inhibited with 79.1%. In comparison to eserine, *S. subspicata* essential oil demonstrated good inhibitory activity of AChE at starting concentrations of 1 and 2 mg/mL (72.82% and 76.89%, respectively), and moderate inhibition of BChE (51,51% i 27,15%, respectively) [52]. *M. pulegium* essential oil at the same starting concentrations showed moderate inhibitory activity with inhibition of AChE (28.8 and 50.6%, respectively) and BChE (63.7 and 71.1%, respectively) [48].

These good results for *S. subspicata* essential oil may be due to presence of the well-known cholinesterase inhibitors α-pinene (10.2%) and β-caryophyllene (14%), among the main components. The moderate inhibitory activity of *M. pulegium* essential oil could be explained by the presence of moderate ChE inhibitor pulegone, as its primary component (54%). 1,8-cineole, a highly strong ACh inhibitor, is also present in *M. pulegium* oil in a smaller amount (0.2%), as well as α-pinene and ß-caryophyllene [51]. It is worth noting that our results reveal better inhibition of less specific BChE than AChE, which has to be further examined.

#### **6. Conclusions**

An excess of reactive species and damage caused by their action is called oxidative stress. In a state of oxidative stress, an excess of ROS and RNS may damage lipids, proteins, carbohydrates, and nucleic acids. Free radicals attack unsaturated fatty acids in biological membranes causing lipid peroxidation. Oxidative modification of proteins is present in diseases and changes associated with the aging process, such as atherosclerosis, tumors, neurodegenerative diseases, and the aging. In addition to fragmentation, oxidation of the amino acid residues increases carbonyl concentration, so the presence of carbonyl groups can be used as an indicator of protein oxidation.

Oxidation of lipid molecules is a major problem in the food industry, as it leads to changes in the organoleptic properties of food, a decrease in its nutritional value, as well as the formation of radical components that can endanger consumers' health. Polyunsaturated fatty acids oxidize much faster than monounsaturated or saturated ones. Lipid autooxidation is an autocatalytic reaction, which means that it progresses over time due to the formation of products that catalyze the reaction themselves.

The use of some synthetic antioxidants has negative effects on human health due to the promotion of carcinogenesis [10, 11], and there is a tendency to replace synthetic antioxidants, where possible, with non-toxic antioxidants of natural origin. More recently, essential oils have also been used as a substitute for synthetic antioxidants, in those food canning sectors where their use does not adversely affect product flavor [12].

Given that the oxidative stress is associated with the etiology and pathogenesis of many diseases, it is believed that eliminating the causes of oxidative stress may prevent or delay the occurrence of pathological changes and reduce the occurrence of diseases. Therefore, natural antioxidants – alone or in the form of extracts – may be useful in the treatment of such diseases. Thus the reason for the great interest in researching the antioxidant activity of aromatic, medicinal, and edible plants [13]. With the exception of some phenolic components, whose antimicrobial and antioxidant activity is well known, such data are not available for most other components of essential oils.

*Biological Application of Essential Oils and Essential Oils Components in Terms of Antioxidant… DOI: http://dx.doi.org/10.5772/intechopen.102874*

Inhibition of acetylcholinesterase prevents the hydrolysis of acetylcholine, thus prolonging its activity in the transmission of nerve impulses. This concept is applied in the treatment of diseases characterized by low ACh levels, such as Alzheimer's disease. Synthetic AChE inhibitors such as physostigmine, tacrine, and donepezil cause side effects such as hepatotoxicity and gastrointestinal disorders. This was an incentive for further research with the aim of finding new ChE inhibitors of natural origin, with greater efficiency and bioavailability, as well as with fewer side effects. Many phytochemicals are bioactive compounds, some of which show ChE inhibitory activity and represent a model for the development of new drugs, ChE inhibitors. As terpenes and terpenoids have shown relatively weak inhibitory capacity in studies published so far, it is necessary to develop analogues with an improved efficiency [21].

The obtained results show that the tested essential oils of *Satureja subspicata* and *Mentha pulegium* growing in Bosnia and Herzegovina contain compounds that, in addition to antioxidant activity, also show activity in terms of cholinesterase inhibition. Therefore, they may be important in the prevention and treatment of Alzheimer's disease and other neurodegenerative disorders, as well as in conditions of impaired homeostasis caused by oxidative stress, and also in food as protecting antioxidants [40, 48].

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Mejra Bektašević1 \* and Olivera Politeo2

1 Biotechnical Faculty, University of Bihać, Bihać, Bosnia and Herzegovina

2 Faculty of Chemistry and Technology, University of Split, Split, Croatia

\*Address all correspondence to: mejra\_b@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 7**

## Pharmaceutical and Therapeutic Potentials of Essential Oils

*Ishrat Nazir and Sajad Ahmad Gangoo*

#### **Abstract**

It is a common perspective that medicinal plants have played and continue to perform an undeniably major role in the lives of people worldwide. Essential oils are the key constituents of medicinal herbs and their biological activities have been discovered since ancient times and are enormously utilised in multiple industries. The essential oils possess important biological properties like antibacterial, antioxidant, antiviral, insecticidal, etc. Because of these unique features they are more acceptable and are utilised in various fields throughout the world. In the cosmetics industry they play an important role in the development of perfumes while in the food industry they have been used as food preservatives. Essential oil components are interestingly utilised for pharmaceutical applications. The most investigated properties are antioxidant, anti-inflammatory, antimicrobial, wound-healing, anxiolytic activities etc. The current thrust area is evaluation for aromatherapy and anti-cancer, as it is noted that essential oils reported in plants may prevent, inhibit, or even reverse formation of cancerous cells. The aim of this chapter is to provide a concise and comprehensive overview on the therapeutic and pharmaceutical potential of essential oils in the current scenario.

**Keywords:** essential oil, therapeutic use, pharmaceutical potential

#### **1. Introduction**

The plants are the main source of food, clothing and shelter. Besides, different materials derived from plants are utilised in treatment against numerous ailments. Due to detrimental effects of synthetic medicines, the herb derived medicines are undergoing revival because of their safe application. Aromatic plants are the source of essential oils, which are volatile substances having essence and properties of the source plant.

The essential oils have been extracted from 60 families of plants from different parts of the world and around 3000 diverse essential oils have been recognised so far. Out of these around 300 are utilised monetarily in the seasoning and scents advertised [1]. The essential oils can be produced in all parts of a plant, mainly by leaves, flowers and stems (Peppermint, Lavender), fruits (Anise), bark (Cinnamon), seeds (Nutmeg). Plants store these components in the glandular cells or pockets which release them with aroma when squeezed or pressed [2]. Essential oil can be extracted by conventional methods: steam distillation, water and steam distillation. However,

the cold or hot pressing, aqueous infusion, solvent extraction, effleurage or the other methods used for extraction of essential oils [3]. Bowles [4] reported that in some cases essential oil content may reach above 10% viz. Nutmeg (*Myristica fragrans*) and clove (*Syzygium aromaticum*) but in general the essential oil content rarely exceeds 1%. Essential oils possess physical properties as they are commonly hydrophobic in nature depicting slight solubility in water, although solubility in non- polar solvents varies, from highly soluble in waxes, alcohol and other weakly polar solvents. Further, the essential oils are commonly pale yellow or colourless but Chamomile (*Matricaria chamomilla*) essential oil is blue in colour. Moreover, they exist mainly in liquid state showing lower density than water except Sassafras, Cinnamon and Clove essential oil which are denser than water. [5, 6]. The principle chemical components are monoterpenes, sesquiterpenes, oxygenated derivatives, aromatic and aliphatic compounds. The complex mixtures of chemical compounds generally comprise of terpenoids, alcohols, ethers, asters, ketones and aldehydes in differential concentrations.

The pharmaceutical and therapeutic properties of plants are attributed to the essential oils and are related to their chemical composition [1]. All over the world researchers have established various pharmaceutical and therapeutic properties of the essential oils from time to time [7–9]. Extensive work has been carried out to utilise essential oils for the cure of multiple infectious diseases through pharmaceutical remedies. Scientific investigations have established that qualitatively 100% pure essential oil free from impurities have the potential to relieve chronic pain, elevate moods, recover defective cells and treat life threatening diseases, common in the world. The broad therapeutic prospective of the plant derived, essential oils have grab attention of the researchers all around to visualise their anti-cancer properties because of the fact that their mode of action is quite diverse than the classic cytotoxic chemotherapeutic agents [10]. Besides, one fascinating feature is their potential as medicines in aroma based therapies or as carriers for drug delivery. In the recent past the aim of essential oils have alternately shifted from culinary use to pharmaceutical and therapeutic use, yet in addition to their application in the fabrication of fragrances and beauty care products [11].

In the current scenario essential oils are gaining importance day by day, reason for this being they are mostly utilised in beverages, food industries, cosmetics and Fragrances industries for making valuable perfumes, beautifying agents, soaps, shampoos or cleaning gel. Also the significant contribution of essential oils is their utilisation in the Agro-food businesses for increasing the sensorial characters of food items [12]. The purpose of this chapter is to make an effort to bring the remedial and pharmaceutical significance of essential oils in light. For this purpose the recent research carried out throughout the world by various researchers has been included in this chapter.

#### **2. Chemical composition of the essential oil**

The chemical composition of essential oils varies plant to plant, the constituents of essential oils are generally volatile and non-volatile in nature therefore are widely categorised into volatile and non-volatile types. Further, the volatile fractions of aromatic oils are chemically constituted by the mono and sesquiterpene components and several oxygenated derivatives along with alcohols, aliphatic aldehydes, and esters, while as the non-volatile fractions are chemically constituted by the carotenoids, fatty acids, flavonoids and waxes [13].

#### *Pharmaceutical and Therapeutic Potentials of Essential Oils DOI: http://dx.doi.org/10.5772/intechopen.102037*

The chemical composition of essential oils is determined by gas chromatographymass spectrometry (GC-MS). This method is simple, efficient and gives fast results. Further, it is a broadly used analytical technique for the determination of essential oils constituents. A GC-MS provides a valid profile of the essential oil components and serves as the fingerprint of any particular batch of essential oil. The peculiar properties of the oils can be reflected from its chemical composition and GC-MS is a reliable technique to indicate the purity of essential oils in most cases [14]. The components of essential oils are delineated below.

#### **2.1 Classes of essential oil compounds and their biological activities**

#### *2.1.1 Hydrocarbon*

The largest group of composites present in essential oils are hydrocarbons. The hydrocarbons are composed of carbon and hydrogen bits. The hydrocarbons which are found in essential oils are placed in a group called Terpenes (monoterpenes: C10, sesquiterpenes: C15, and diterpenes: C20). On the basis of physical composition the Terpenes may be ambrosial, alicyclic (monocyclic, bicyclic or tricyclic) or acyclic. The terpenes which are ingredients of essential oils are β-pinene, α-sabinene, myrcene, α-pinene, p-cymene, myrcene, α–phellandrene, pmenthane, thujane, fenchane, Limonene,, azulene, cadinene, sabineine and farnesene These composities have been associated with various remedial conditioning (**Table 1**).

#### *2.1.2 Esters*

Esters are the chemical composites constituting an organic or inorganic acid with one hydroxy group replaced by an alkyl group. The Esters are generally found


#### **Table 1.**

*Chemical nature of essential oil compounds and some biological activities.*

composites in a vast number of the essential oils and are known for their affable smell and give sweet smell to the essential oils. The common ester bearing essential oils include linalyl acetate, geraniol acetate, eugenol acetate and bornyl acetate. Esters are anti-inflammatory, spasmolytic, dreamy, and antifungal (**Table 1**).

#### *2.1.3 Alcohols*

Alcohol containing essential oils has a affable type of fragrance. The alcohol bearing essential oils are therapeutically most profitable essential oil components with no reported contraindications. Linalool, menthol, borneol, santalol, nerol, citronellol and geraniol are some important alcohols found in the essential oils. They are known to retain antimicrobial, antiseptic, tonifying, balancing and spasmolytic parcels (**Table 1**).

#### *2.1.4 Phenols*

These are aromatic alcohols which are chemically veritably reactive, slightly poisonous and induce irritation to the skin and the mucous membranes. They exist as crystals at room temperature. The important essential oils containing phenol s are thymol, eugenol, carvacrol and chavicol. The essential oils containing phenols as their constituents possess following characteristics, antimicrobial, rubefacient properties, stimulate the immune and nervous systems and may reduce cholesterol (**Table 1**).

#### *2.1.5 Ketones*

Ketones such as carvone, menthone, pulegone, fenchone, camphor, thujone and verbenone are some common examples of ketones found in essential oils. These groups of compounds are chemically stable and lack fragrance or flavour like the other group of compounds. Besides some remidial effects, Ketones have been reported to retain neurotoxic and abortifacient effects in some cases similar as camphor and thujone [23]. These ketone bearing essential oils have been reported to be mucolytic, cell regenerating; opiate, antiviral, analgesic and digestive in nature (**Table 1**).

#### *2.1.6 Aldehydes*

Aldehydes found in essential oils include citral (geranial and neral), myrtenal, cuminaldehyde, citronellal, cinnamaldehyde and benzaldehyde. Unlike ketones aldehydes retain sweet, pleasant fruity odours and are present in common culinary herbs such as cumin and cinnamon. This group of compounds are unstable and oxidise easily, besides numerous of the aldehydes have been reported to act as mucous membrane irritants and are skin sensitizers. As far as therapeutic use is concerned, aldehydes have been reported to work as antiviral, antimicrobial, tonic, vasodilators, hypotensive, calming, antipyretic and spasmolytic (**Table 1**).

#### **3. Mechanism of action of bioactive components of essential oils**

The mode of action of essential oils varies. The mode of action depends upon chemical composition and molecular structure of the components of essential oil.

#### **3.1 Antibacterial action**

An important feature of essential oils are their hydrophobicity, which allows them to partition into lipids of the cell membrane of bacteria disrupting the structure thus making it more permeable resulting in leakage of ions and cellular molecules which cases greater loss of cell contents leading to cell death for instance trans-cinnamaldehyde can inhibit the growth of E. coli and *Salmonella typhimurium*. It has been reported that essential oils containing primarily aldehydes and phenols for example cinnamaldehyde, citral, carvacrol, eugenol andthymol are characterised by maximum antibacterial activity followed by essential oils consisting of terpene- alcohols.

#### **3.2 Antifungal action**

Antifungal actions resemble in mode of action as those described for bacteria. In case of yeast it has been reported that potential of Hydrogen (pH) gradient across the cytoplasm membrane and blockage of energy production in the cells results in disruption of fungal membranes leading to death. Antifungal effects were caused by a combination of essential oils of clove and *rosmarinus officinalis* against *C. albicans*. Trans-anthole, a major component of Anise essential oil, demonstrated anti-fungal activity against the filamentous fungus, *Mucor mucedo*. The essential oil obtained from citrus containing active component limonene has been reported to inhibit the growth of *Aspergillus niger* by causing deleterious morphological alterations that is loss of cytoplasm fungal hyphae and budding of hyphal tip [24]. Also, tea tree essential oil containing components has been reported to alter permeability as well as membrane fluidity of *Candida albicans* [25].

#### **3.3 Antiviral activity**

The essential oil of saltolinia showed antiviral activity against HSV-1 and HSV-2 by preventing cell to cell virus spread in infected cells. The oil directly inactivated virus particles thus preventing adsorption of virion to host cells. Iso-borneol, a common monoterpene alcohol, showed dual virucidal activity against HSV-1, specifically inhibited glycosylation of viral polypeptides. The antiviral activity of the essential oil is principally due to direct virucidal effects (by denaturing viral structural proteins or glycoproteins). Proposed mechanisms suggest that essential oils intrude with the virus envelope by inhibiting specific processes in the viral replication cycle or by masking viral factors, which are necessary for adsorption or entry into host cells, therefore precluding cell-to-cell virus prolixity [26]. The essential oils attained from oregano and clove have been reported to show remarkable antiviral exertion against a number of non-enveloped DNA and RNA viruses including adenovirus type-3, coxsackievirus B-1 and polio virus. Several constituents of essential oils like monoterpenes, sesquiterpenes and triterpenes have been reported to show strong antiviral activity against rhinovirus and herpes virus. The essential oil components of pogostemoncablin have been found active against H2N2 influenza-A virus [27].

#### **3.4 Anticancer activity**

The broad therapeutic prospective has gained a lot of attention throughout the world in recent times for their implicity capacity in relation to combating

cancer. According to Wu et al. [28] diallyl sulphide, diallyldisulfide composites actuated in the host cells (rats) the enzymes which play an important part in the detoxification process of hepatic phase-1 (decomposition of chemical bonds that link carcinogenic toxins to each other) and phase-2 (bonds to toxins released detoxifying enzymes similar as glutathione S- transferase). Further myristicin an allyl benzene composites found in the essential oil of nutmeg activates glutathione S- transferase in mice cells which minimise carcinogenesis induced by benzo a pyrene in the lungs of mice. Moreover it has been recently concluded that myristicin persuade apoptosis in neuroblastoma (SK-N-SH) in humans [18]. Geraniol have been reported to decrease the resistance of: cancer cells (TC 118) to 5-fluorouracil an anticancer agent. Further, geraniol enhances the inhibitory effect of tumour growth 5-fluorouracil. Moreover the essential oil of balsam fir which contains alpha-humulene depicting high anticancer property in several cell lines and low toxicity to healthy cells [29]. In addition to this limonene an active component of citrus essential oil has been reported to show anticancer activity at the level of stomach cancer and liver cancer [30]. Chamomile essential oil containing an active component alpha-bisabolol sesquiterpene alcohol has been reported to show antigliomale activity [31].

### **4. Therapeutic properties of some essential oils**

#### **4.1 Chamomile essential oil (***Matricariachamomilla***)**

It has been reported that Bisabolol and chamazulene are active compounds found in chamomile essential oil. The dry flowers of Chamomile have numerous properties such as anti-inflammatory, antioxidant and also possess some mild astringent properties [32–35].

#### **4.2 Anise essential oil (***Pimpinellaanisum***)**

The Anetholeis is the main active compound found in ansine essential oil. Therapeutic Properties of Anise include a cure for sleeplessness, an appetite stimulant and diuretic. In ancient times the Anise has been reported to show the carminative property (reducing flatulence) [36–38].

#### **4.3 Nutmeg essential oil (***Myristicafragrans***)**

The Main active compounds found in nutmeg essential oil are Sabinene, 4-terpineol and myristicin. The essential oil of Nutmeg has been found effective against a number of microbial agents and pests. Also, it is used as an important ingredient to cough syrups, while in some instances it acts as general tonic for brain activity and normal functioning of circulatory system [39].

#### **4.4 Cedar essential oil (***Cedruslibani***)**

Cetin et al. [40] reported that the principle active component of cedar essential oil is Limonene. The essential oil of cedar has been found to perform Antifungal and Larvicidal activity. Also, the oil is good for regeneration of blood cells and enhances the healing property [41–43].

#### **4.5 Dill essential oil (***Anethumgraveolens***)**

The Main active compound found in dill essential is Carvone and the well-established therapeutic use of essential oil reported is the Antispasmodic in gastrointestinal disorders. Moreover, it reduces the fluidity of bronchial secretions in the lungs and thus prevents various lung infections [21, 44].

#### **4.6 Garlic essential oil (***Allium sativum***)**

It has been reported that Diallylle disulphide is the main active compound found in garlic essential oil. Garlic essential oil Protects and maintains the cardiovascular system, reducing blood pressure. Also, the extracted essential oil has been reported to control the fungal infection, pest infestation and parasitic growth. Moreover, many studies have found an increase in garlic intake reduces the cancers of the upper digestive tract [45].

#### **4.7 Clove essential oil (***Syzygiumaromaticus***)**

Eugenol and eugenyl acetate are the main active compounds which constitute clove essential oil. The commonly known therapeutic property of essential oil reported is effectiveness against the tooth ache and as an analgesic for alveolar osteitis. Also, the studies have proven that essential oil obtained from clove is effective against various microbial and fungal infections [46, 47].

#### **4.8 Cinnamon essential oil (***Cinnamomum cassia***)**

Essential oil of Cinnamon is mainly constituted by the chemical Cinnamaldehyde. The cinnamon essential oil has been reported to perform enormous functions related to health. The studies have established that it lowers the plasma glucose in the diabetic patients. Also, it has been reported to lower the level of total cholesterol and triglycerides in the blood, thus preventing cardiovascular diseases [48, 49].

#### **4.9 Sweet orange essential oil (***Citrus sinensis***)**

Limonene is Main active compound found in sweet orange essential oil. It possesses. Antiseptic property in some cases but the commonly reported property of essential oil is used as an excellent flavouring ingredient in the food industry [50, 51].

#### **4.10 Eucalyptus essential oil (***Eucalyptus globulus***)**

A number of compounds has been reported in the eucalyptus essential oil but 1,8-cineole is the major constituent present in the essential oil. A number of studies have concluded that it can be used for treating cough, common cold and to mildly relieve muscular pain. Also, the essential oil is used as an insect repellent and biopesticide in many countries [52, 53].

#### **4.11 Peppermint essential oil (***Menthapiperita***)**

The major portion of essential oil contains menthol and menthone compounds, which govern the properties like treatment for irritable bowel syndrome. Also, used topically for muscle pain, nerve pain and relief from itching in many cases. Moreover, it has been found to minimise the mucosal irritation in the digestive tract and reduce the heartburn [51, 54, 55].

#### **4.12 Lavender essential oil (***Lavandulaofficinalis***)**

Linalool and linalyl acetate are main active compounds found in lavender essential oil. The main properties of lavender essential oil includes sedative action, pan relaxing, analgesic in many cases and effective in alleviating in anxiety and sleep disturbances [56–59].

#### **4.13 Tea tree essential oil (***Melaleucaalternifolia***)**

The main active compound reported so far in the essential oil has been only Terpinène-1-ol-4. The tea tree essential oil has been used to treat coughs and colds widely. In addition, the oil is used to treat sore throats and numerous skin ailments [60–62].

#### **4.14 Lemon essential oil (***Citrus limonum***)**

Limonene is the main constituent compound found in lemon essential oil. The therapeutic Properties include enhancement of natural immunity in the human body, regulation of metabolism and a reliable nerve tonic. Besides, it has been concluded through many studies that essential oil acts as antiviral and antimicrobial [63–66].

#### **4.15 Yarrow (***Achillea millefolium***)**

The important active constituents of yarrow essential oil are Sabinene and terpineol manifesting. A number of studies have reported that the essential oil of yarrow acts as an anti-inflammatory and analgesic. Moreover, it has been found to cure many lung diseases and act as an important antiseptic agent [67, 68].

#### **4.16 Geranium (***Pelargonium graveolens***)**

The geranium essential oil consists of citronellol, geraniol, linalool and citronellylformate. The essential oil has been found to depict astringent and antiseptic properties. Also, in minor instances anti-inflammatory and antioxidant property has been observed [69].

#### **4.17 Thyme (***Thymus vulgaris***)**

Chromatographic analysis has revealed that the main active compound in essential oil is thymol followed by carvacrol, linalool etc. Thymol shows antiseptic properties and is an active ingredient of commercially prepared mouthwashes and toothpastes.

#### **5. Conclusion**

This chapter comprehensively summarises the therapeutic and pharmaceutical potential of essential oils. The essential oils possess important biological activities which lead to their application in diverse fields. The characteristic properties such

#### *Pharmaceutical and Therapeutic Potentials of Essential Oils DOI: http://dx.doi.org/10.5772/intechopen.102037*

as antiviral, anti-bacterial, anti-fungal, anti-inflammatory, ant carcinogenic etc. are utilised in various industries to prepare beneficial products which have great impact on human life. The active compounds present in essential oils are thoroughly studied now a day for replacement to unsafe medications. In pharmaceutical industries the use of essential for making perfumes and other pharmaceutical products are gaining popularity. Therefore, the essential oils are receiving attention from all the corners because of their tremendous features. Thus essential oils and their constituents can arguably be studied in the future for meticulously more scientific investigations and probable applications as important components in future medical field and pharmaceutical industries.

### **Author details**

Ishrat Nazir\* and Sajad Ahmad Gangoo Faculty of Forestry, SKUAST-Kashmir, Benhama, Jammu and Kashmir, India

\*Address all correspondence to: ishratnazir12345@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 8**

## Application of Essential Oils in the Treatment of Inflammatory Bowel Disease

*Najmeh Oliyaei, Nader Tanideh and Seyedeh Zahra Nasirifar*

#### **Abstract**

Essential oils (EOs) are natural compounds obtained from algae and different parts of plants. EOs are volatile secondary metabolites and are classified into major groups, including terpenes/terpenoids and aromatic/aliphatic compounds. There are numerous studies about the biological activities of EOs, demonstrating their abilities for the prevention and treatment of diseases. Their biological activities are mainly related to their constituents, such as α-pinene, thymol, 1, 8-cineole, carvacrol, etc. Thus, the use of EOs as pharmaceutical agents for curing several diseases has gained much attraction in recent years. Moreover, inflammatory bowel disease (IBD) is a type of disease that causes chronic inflammation in the intestine. Ulcerative colitis (UC) and Crohn's disease (CD) are two main forms of IBD. Some studies have reported the efficacy of EOs in treating IBD, in particular, UC. This chapter will focus on the biomedical application of EOs in the treatment of IBD.

**Keywords:** bioactive compounds, essential oils, biological properties, inflammatory bowel disease, ulcerative colitis

#### **1. Introduction**

Inflammation is a physiological response against various infection agents, toxins, and injury which are related to several disorders [1]. Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are two common disorders with similar signs of abdominal pain but different pathophysiology and therapeutic methods. IBD causes inflammation of the intestines and is a term for a broad spectrum of diseases and crohn's disease (CD) and ulcerative colitis (UC) are the most common. IBD treatment usually needs a lifetime of medical care, while IBS affects the large intestine without inflammation [2, 3]. Moreover, IBD affects 6.8 million people worldwide, in particular in North America and United Kingdom [4]. The genetic predisposition, gut microbiota, environmental risk factors, and dysfunction of the immune system can be related to IBD. The IBD is characterized by intestinal epithelial injury (excess mucus production), inflammation expansion, and failed control of the inflammatory response [5]. Furthermore, it has been established that the gut microbiota has an important effect on IBD pathology as their close connection to the host immune system [6]. The usual approach and therapeutic management strategies for IBD are drug treatment by monoclonal antibodies, immunomodulators, corticosteroids, and aminosalicylates which may have some side effects [4]. Therefore, the development of a safe and effective strategy is required for the treatment of IBD patients [7]. The novel treatment of gastrointestinal diseases is utilizing natural bioactive compounds such as crude extracts, essential oils (EOs), and pure isolated compounds from medicinal plants with improving immune function attributes [8]. Thus, natural bioactive compounds with anti-inflammatory effects such as herbal medicine extracts [9, 10] and EOs have attracted much attention to develop new types of anti-inflammatory agents [11]. There are several investigations confirmed the antiinflammatory effect of the herbal medicine extracts or EOs in different UC models animal models [12–15]. It has been established that EOs can improve the balance of gastrointestinal immunity by their anti-inflammatory activity and downregulation of pro-inflammatory products [16].

EOs are highly volatile secondary metabolites and are known as aromatic substances produced by specific plants [17] or algae species [18]. EOs have considerable potential to be used as a part of pharmaceuticals, nutraceuticals, and functional foods because of their broad range of biological activities [17]. EOs are involved in monoterpenes, sesquiterpenes, and oxygenated derivatives of these and possess synergistic effects in combination together. The usual extraction methods of EOs are steam distillation, hydrodistillation, or solvent extraction. However, there are numerous factors are known to influence the properties of EOs including species and genetic, climate, and geographic origin which caused differences in chemical structures [19]. Moreover, the different chemical structures of EOs exhibit different biological properties [20]. A growing interest in using natural bioactive compounds as medicine or food preservation results in increasing interest in EOs applications. They are characterized by their potential health benefits including antibacterial, antifungal, antiviral, insecticidal, and antioxidant activities. These attributes are related to single or groups of compounds, which play an important role in the defense mechanisms of plants against abiotic stress [21].

This chapter presents an overview of EOs potential effect in promoting health, in particular, IBD.

#### **2. Inflammatory bowel disease (IBD)**

IBD is a group of diseases that caused diarrhea, abdominal pain or discomfort, and even bloody stool. These inflammatory intestinal diseases are involving the ileum, rectum, and colon. The two main forms of IBD are UC and CD with different clinical, pathogenic, and biomolecular properties. Some investigations reported that IBD is a heterogeneous medical condition distinguished by inflammation of the gastrointestinal tract due to the unusual response of aggressive types of T-cells to luminal microbiota in genetically susceptible patients [3]. Several mediators involved in inflammation and immune responses are represented to impact on IBD, including pro-inflammatory cytokines including tumor necrosis factor (TNF), Interferons (IFN-γ), interleukins (IL-6, IL-12, IL-21, IL-23, IL-17) and anti-inflammatory cytokines (IL-10, TGFβ, IL-35, etc.). CD is usually characterized by an increased secretion of IL-12, IL-23, IFN-γ, and IL-17 by Th1 and Th17 cells while Th2 and Th9 cells are considered in UC by secretion of IL-13, IL-5, and IL-9. Several studies were investigated about cytokines effects in initiating, mediating, perpetuating, and controlling intestinal

#### *Application of Essential Oils in the Treatment of Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.102966*

inflammation and tissue injury because they are the crucial parameters in the pathogenesis of IBD and may have potential therapeutic targets [5]. In addition, NLRP1, NLRP3, NLRC4, absent-in-melanoma 2, and pyrin (types of pattern-recognition receptors (PRRs)), construct inflammasomes. NLRP3, one of the NOD-like receptor family member, has been investigated more than other inflammasomes intimately pertinent to IBD. The principal clinical expressions of most patients with IBD consist of uncommon levels of the NLRP3 inflammasome and pro-inflammatory cytokines [22]. Moreover, oxidative stress has been shown to participate in major mechanisms of some disorders such as IBD. Uncontrolled and persistent oxidative and nitrosative stress with overproduction have an important effect on chronic disorders such as IBD as can be seen in **Figure 1** [24]. The principal ROS consist of superoxide anion (O2), nitric oxide (NO), hydroxyl radical (− OH), hydroperoxyl radical (O2H), hydrogen peroxide (H2O2), and singlet oxygen (O2) [25]. Antioxidant equilibrium can eliminate the harmful effects of ROSs and RONs. They classify intracellular and plasma antioxidant mechanisms [23].

#### **2.1 Risk factors**

There are several risk factors of IBD, including lifestyle, age, genetic and immune response. Diet, in particular, meats and oily foods, and exposure to different contaminations and antibiotics may change the gut microbiota resulting in IBD. While consumption of vegetables, fruits, and fish can reduce the risk of IBD. Indeed, various food products may change gut permeability and cause dysfunctional intestinal mucosa [26]. Patients diagnosed with IBD also have the lower health-related quality of life and risk factor for colon cancer [27]. Meanwhile, it has been established that functional foods rich in grape seed oil [28] extra virgin olive oil, canola oil, and rice bran oil [29] or herbal medicine extract such as *Pistacia atlantica* [27] are preferable means for overcoming the limitations of the current drug treatments of UC. In addition, various intestinal immune cells are responsible against foreign antigens

#### **Figure 1.**

*The source of ROS formation and effects of ROS accumulation [23].*

and secret some pro-inflammatory mediators as a result of their activation. However, upregulation of these pro-inflammatory mediators caused perpetuates the intestine's inflammatory response in these conditions. Therefore, overexpression of pro-inflammatory cytokines plays a crucial role in IBD. However, the types of inflammatory reaction of the immune response are different in CD and UC [30]. Thus, the utilization of anti-inflammatory bioactive compounds is a safe approach for the treatment of IBD by regulating pro-inflammatory mediators.

#### **3. Essential oils (EOs)**

EOs are volatile compounds that are found in different parts of medicinal and herbal plants. Most of the EOs are known as generally recognized as safe (GRAS) and can be used as food preservatives or flavoring agents. EOs consist of various active constituents with numerous biological properties that are influenced by their chemical diversity and quantities [31]. EOs are more complex and comprise several components at different concentrations. They are defined by some main constituents at relatively high concentrations (> 20%) compared to other components present in trace amounts. EOs are classified into two main groups including terpenes/terpenoids and aromatic/aliphatic compounds. The various biological attributes of EOs are related to their major compounds [32]. In addition, phenolic compounds, plant secondary metabolites which consist of a minimum aromatic ring with at least one or more hydroxyl groups, are sub-classified into two groups: flavonoids and nonflavonoids. Flavonoids are subdivided into many groups comprising flavones, flavan-3-ols, dihydrochalcones, dihydroflavonols, flavonols, flavanones, proanthocyanins, anthocyanins, chalcones, isoflavones, and aurones. Non-flavonoids comprise phenolic acids, stilbenes, lignans, coumarins, curcuminoids, and tannins. The important source of phenolic compounds are nuts, soy products, cocoa, vegetables, cereals, red wine, soy products, whole grains, and olive oil. Cardio-protective and anti-inflammatory traces of polyphenolics have been studied and probably have a positive effect on IBD and IBS [4]. **Figure 2** depicts the chemical structure of some constituents of EOs.

EOs have recently gained increasing attention with their potential biological activates and have been largely used in the pharmaceutical industry as safe and natural

**Figure 2.**

*Some of the main bioactive constituents of EOs.*

#### *Application of Essential Oils in the Treatment of Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.102966*

medicines. They are well recognized to possess antioxidant, anti-inflammatory, antimicrobial, antiviral, and anticarcinogenic properties [33]. Recently, some investigations confirmed that EOs from various plants have anti-inflammatory activity by reducing or inhibiting of the production of pro-inflammatory mediators [34]. EOs exhibit their anti-inflammatory mechanisms by reducing the gene expression of proinflammation cytokines (TNF-α, IL-1β, IL-6 and IFN-γ) and enzymes such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2) and Myeloperoxidase (MPO) which caused upregulation of inflammatory responses.

#### **3.1 Essential oils anti-inflammatory activity**

Numerous investigations reported that intake of EOs appeared to have protective activity against pro-inflammatory products. For instance, Amorim et al. [35] suggested that *Citrus* species EOs possess anti-inflammatory activity. This study showed that the *C. limon*, *C.latifolia*, *Citrus aurantifolia* and *C. limonia* (10–100 mg/kg, p.o.) EOs caused reducing the cytokines mediators such as TNF-α, interleukin-1β (IL-1β), and interferon-γ (IFN-γ) in carrageenan-induced inflammation in a subcutaneous air pouch (SAP) model. The anti-inflammatory activity of *C. limon* and *C. limonia* might be related to the high amounts of limonene. Another study suggested significantly decreased IL-6 secretion by *Pinus* EOs. They explained that the low concentration (0.01%) of *Pinus heldreichii* Christ (Pinaceae), *Pinus peuce* Griseb and *Pinus mugo* EOs can decrease the IL-6 production up to 60%. The EOs of *Pinus* mainly consist of α-pinene [34]. The chemical structure of EOs from leaves of *Ocimum basilicum*, *Ocimum americanum*, *Hyptis spicigera*, *Lippia multiflora*, *Ageratum conyzoides*, *Eucalyptus camaldulensis* and *Zingiber officinale* was also investigated. α-terpineol (59.78%) and β-caryophyllene (10.54%) for *O. basilicum*; 1, 8-cineole (31.22%) and camphor (12.730%) for *O. americanum*; β-caryophyllene (21%) and α-pinene (20.11%) for *H. spicigera*; p-cymene (25.27%), β-caryophyllene (12.70%), thymol (11.88) for *L. multiflora*; precocene (82.10%) for *A. conyzoides*; eucalyptol (59.55%) and α-pinene (9.17%) for *E. camaldulensis*; arcurcumene (16.67%) and camphene (12.70%) for *Z. officinale* were determined as the main compositions of EOs which have impact on their antioxidant and anti-inflammatory attributes. Among all EOs, *Z. officinale* (0.4 mg/ml) showed the highest anti-inflammatory activity by 50.9% of inhibition of lipoxygenase. The anti-inflammatory activities were investigated according to the prevention effect of lipoxygenase which plays a significant role in several human cancers [36]. A study also investigated the anti-inflammatory attributes of *Thymus vulgaris* EOs. They found that EOs can cease the 5-lipoxygenase activity and lower the TNF-α, IL-1β, and IL-8 secretion in THP-1 cells [37]. Siani et al., [38] also investigated the anti-inflammatory activity of *Syzgium cumini* and *Psidium guajava* EOs in lipopolysaccharide (LPS)-induced pleurisy model. Both types of EOs showed anti-inflammatory properties via prevention influence on eosinophil and, to a lesser extent, neutrophil and mononuclear cell migration. This effect of *Syzygium cumini* and *P. guajava* mainly is contributed to their compositions including limonene, ocimenes, α-pinene, and caryophyllene-type sesquiterpenes. Furthermore, some substances have synergistic effect in combination together such as α-pinene and mono- or sesquiterpenes [38]. Thymus EOs decreased the gene expression of nuclear factor-kappa (NF-k)B, COX-2 and iNOs, consequently causing lower production of NO and TNF-α [39]. The carvacrol and thymol are two main constituents of thyme EOs which are responsible for thyme anti-inflammatory attributes by inhibiting of cyclooxygenase activity and NO production [40]. Similar observations were revealed

about the anti-inflammatory properties of *T. caespititius* [41] and *Thymus pulegioides*, *T. praecox* subsp. *polytrichus*, *T. vulgaris*, *Thymus serpyllum* subsp. *serpyllum*, *T. longicaulis*, *T. striatus* extracts [42]. Moreover, EOs isolated from algae have anti-inflammatory activity as Dhara and Chakraborty [43] reported that xenicane-type diterpenoid from *Sargassum ilicifolium* exhibit the inhibitory effect against pro-inflammatory enzymes such as 5-lipoxygenase and COX-2.

#### **3.2 Protocols of inflammatory bowel disease treatment by essential oils**

There are several studies about the therapeutic and pharmaceutical attributes of EOs related to various diseases [43]. An alternative approach to the treatment of IBDs in the administration of EOs and several investigations are presented in **Table 1**.





#### **Table 1.**

*Treatment of inflammatory bowel disease by essential oils.*

Yu, et al. [44] investigated the anti-inflammatory effect of *Atractylodes lancea* EOs against UC *in vitro*. They proved that Atractylodes lancea EOs can downregulate the level of IL-6, IL-8, IL-12, IL-1-β, TNF-α, NO, p-IKK-α, p-IKK-β, and NF-κB human colonic epithelial (HcoEpiC) cells induced by LPS- epithelial cells. IKK/NF-κB signaling pathway was the *in vitro* mechanism.

In *vivo* experimental studies have shown the therapeutic effects of EOs on UC inflammation. In 2016, Rashidian, et al. [50] conducted a study of the meliorative effect of *O. basilicum L.* EO after two doses in acetic acid-induced rat model. The results showed that the treatment with 200 and 400 μL/kg of EO caused a significantly reduction in the ulcer severity, ulcer area, and ulcer index and confirmed the protective activity of EOs. Moreover, *Lavender* EO has also been shown to improve colonic mucosal injury in dextran sulfate sodium (DSS)-induced UC mice by reducing the inflammatory cytokines levels such as in serum and colon tissue's EGFR, TNF-α, and IFN-γ. The key pathway in the UC treatment is the Th17 cell differentiation, PI3K-Akt signaling pathway, and Th1 and Th2 cell differentiation of lavender EOs [16]. Estrella, et al. [8] also demonstrated that Limonene from *Agastache mexicana* EO has a potential effect on improving the UC in Swiss Webster mice. They investigated the *A. mexicana* ssp. *mexicana* EO (3–300 mg/kg) activity in an oxazolone-induced colitis model. According to the results, limonene possessed antioxidant and anti-inflammatory bioactivity that caused downregulation of the iNOS, COX-2, PGE2, TGF-β, and ERK1/2 signaling

#### *Application of Essential Oils in the Treatment of Inflammatory Bowel Disease DOI: http://dx.doi.org/10.5772/intechopen.102966*

pathway. Thus, EOs prevented intestinal tissue damage and reduced myeloperoxidase activity, macroscopic damage reducing and inhibition of cytokines expressions such as IL-1, IL-6, TNF-α, and INF-γ. Moreover, EOs have antinociceptive attributes resulting in lower pain in the UC in human. It has been suggested that 200 and 400 mg/kg of *F. vulgare* EOs decrement the TNF-α positive cells expression of colon tissue. They have a considerable effect on rat inflammatory of acetic acid-induced colitis by the prohibition of NF-kB pathway [54]. Furthermore, it has been reported that both *Carum carvi L.* (caraway) EOs and hydroalcoholic extract own anti-inflammatory properties in colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats. The ulcerative lesion index would be prevented by 100–400 μl/kg orally administration of *C. carvi L.* EOs. The inflammatory cytokines and chemokines can be reduced by the caraway terpenoid, flavonoids, fatty acids, triacylglycerols, polysaccharides, lignin, and polyacetylenic compounds, resembling the glucocorticoids mechanism. It seems that caraway reduces the production of prostaglandin E2 and increases the production of leukotriene B4 in human polymorphonuclear leucocytes [49]. A similar observation was reported by Minaiyan, et al. [47] who study the anti-colitis activity of *Rosmarinus officinalis* L. EOs (100, 200, and 400 μl/kg) and extract (100, 200, and 400 mg/kg) in rats colitis induced by TNBS. Moreover, 100–400 mg/kg of *Pelargonium graveolens* EOs own doseindependent anti-inflammatory potential in acetic acid-induced rat UC induced by acetic acid thus *P. graveolens* EOs diminish the oxidative stress by inhibiting the production of free radicals, and in the end preventing the increase of inflammation [52].

By adjustment of intestinal microflora, EOs effect on IBD. For example, *cinnamon* EOs administration amends the diversity and richness of the intestinal microbiota, reduces in *Helicobacter* and *Bacteroides,* and increase in Bacteroidales\_S24–7 family in mouse colitis induced by DSS. There is a positive correlation between TNF-α with *Helicobacter.* It seems that the protective attributes of *cinnamon* EOs against IBD is attributed to cinnamaldehyde [48]. EOs of *R. officinalis* also is full of terpenes and 1.8-cineole is the main compound of its EO by antinociceptive and anti-inflammatory trace. This terpene remarkably prevents the production of cytokines in lymphocytes and monocytes [51].

#### **4. Conclusion**

EOs are a blend of volatile, aromatic, and natural substances extracted as secondary metabolites from different parts of plants or algae. EOs have a great potential to be used as a part of pharmaceuticals, nutraceuticals, and functional foods because of their broad range of biological activities. In the recent years, EOs have gained much attention due to their antioxidant and anti-inflammatory attributes. The present chapter revealed encouraging results about numerous EOs being used in different IBD and UC animal models. IBD and its attributed disorders such as CD and UC dramatically increase in recent years because of various reasons such as age, genetics, immune response, and lifestyle, in a particular diet. While several studies confirmed that the EOs exhibit anti-inflammatory effects via in downregulation of gene expression of cytokines pro-inflammatory and related enzymes. This chapter suggests the utilization of EOs as healthy food ingredients or dietary supplements with anti-inflammatory characteristics.

#### **Conflict of interest**

The authors declared no conflict of interest.

### **Author details**

Najmeh Oliyaei1 , Nader Tanideh1,2\* and Seyedeh Zahra Nasirifar3

1 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Faculty of Nutrition Sciences and Food Technology, Department of Food Science and Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

\*Address all correspondence to: tanidehn@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 9**

## *Teucrium ramosissimum* Derived-Natural Products and Its Potent Effect in Alleviating the Pathological Kidney Damage in LPS-Induced Mice

*Fatma Guesmi and Ahmed Landoulsi*

#### **Abstract**

*Teucrium* esssential oil mediates an extensive spectrum of biological effects, including renal diseases. The aim of this research was to explore the ethnobotanical feature, biochemical composition and antiinflammatory potential of *T. ramosissimum* alone or prior the use of LPS-induced kidney damage. The essential oils were subjected to Gas chromatography-mass spectrometry (GC/MS) apparatus to detect biomolecules in *T. ramosissimum*. *In vivo* renal dysfunction induced by LPS was investigated using mouse model. Our data showed that oral treatment of animals with LPS highly increased level of serum biomarkers and induces renal dysfuntion, whereas, pre-treatment with *T. ramosissimum* mediated markedly histopatological changes of kidney architecture and ameliorates renal function. Dense cover of secretory structures in *teucrium* leaves may protect this specie. Overall, this study showed phytocompounds richness and interesting biological activities of Tunisian *Teucrium ramosissimum*. Essential oil of this specie *T. ramossimum* given prior to LPS exposure protected mice from renal inflammation.

**Keywords:** *Teucrium ramosissimum*, essential oil, hairs, LPS, renal dysfunction

#### **1. Introduction**

The genus *Teucrium L.* (Lamiaceae) is a genus growing in mild climate zones, particularly in the Mediterranean Basin and Central Asia [1]. Limited number of in-depth scientific researches have been done so far on the phytochemistry and bioactivities [2] of *Teucrium* genus that is represented by herbs or shrubs, with tubular or campanulate calyx, 2-lipped or actinomorphic, 5-toothed, the teeth equal or the upper larger; corolla with one 5-lobed lip; tube without a ring of hairs inside, often included in the calyx; and nutlets smooth or reticulate [1].

*Teucrium* species have been used in phytopharmacology, helping to treat many diseases, including tuberculosis, gastrointestinal disorders, inflammations, rheumatism, and diabetes [3]. The widespread applications of *Teucrium* genus in the ethnomedicine

of several countries [1] may be due to its richness in biocompounds used in *in vivo* and *in vitro* biological effects. Moreover, traditional health care systems based on plants and plant-derived products are highly popular and employed therapeutically [2] in Tunisia. The plant essence that contains several secondary metabolites is synthetized in all parts (leaves, flowers, stem, seeds, buds). The use of essential oils in industries are markedly increased, including the beverage, food, aromatherapy, cosmetics and personal care [4]. Moreover, the recent trend in the field of inflammation research is to search for alternative therapeutic agents from natural sources that are devoid of the adverse effects characteristic for conventional steroids or nonsteroidal anti-inflammatory drugs (NSAIDs). In this context, phytochemical studies and biochemical investigations on the mode of action of traditional complementary remedies are of utmost importance [2]. Acute kidney damage, a great public health problem, has been grown in the world. It's a critical care syndrome and an abrupt loss in renal function [5], resulting in acute reduction of renal activity and up to 22% mortality of hospitalized patients. Acute kidney injury is estimated to occur in about 20–200 per million population in the community, 7–18% of patients in hospital, and approximately 50% of patients admitted to the intensive care unit (ICU) [6]. Lipopolysaccharide (*Escherichia coli* 055:B5) is one of the most important causes of sepsis and is involved in the pathogenesis of sepsis-associated acute kidney injury (SA-AKI), which may lead to "cytokine storm," intensified oxidative stress, low blood pressure, renal hypoperfusion, and finally a gradual decline in renal function [7].

*T. ramosissimum* belongs to the Lamiaceae family, of the genus *Teucrium* is known as "Hchichet Belgacem" or "Hchichet Ben Salem" in the region of Gafsa in the southwest of Tunisia [8]. The specie is present in the South of Tunisia in particular in Djebel Orbata (Zannouch-Gafsa, Tunisia) and Bou Hedma Mount (Sidi Bouzid-Tunisia). It exists as a small sub-shrub, bushy, of silver gray, 8–15 cm tall. The stems are slender, erect and small. While, the leaves are white, with rounded limb with 7 deep crenellations. The inflorescence is pauciflor; the white calyx is 4 mm long, with long acute and sub-natural teeth [8]. Three sesquiterpenoids (teucmosin, 4α-hydroxy-homalomenol C, 1β,4β,7αtrihydroxy-8,9-eudesmene), five sesquiterpenoids (oplopanone, homalomenol C, oxo-*T*-cadinol, 1β,4β,6β-trihydroxyeudesmane, 1β,4β,7α-trihydroxyeudesmane) and two trinorsesquiterpenoids (4β-hydroxy-11,12,13-trinor-5-eudesmen-1,7-dione and 1β,4βdihydroxy-11,12,13-trinor-8,9-eudesmen-7-one) were isolated from the ethanolic extracts of the aerial parts of *Teucrium ramosissimum* [9]. *Teucrium ramosissimum* is particularly present in the higher mounts of southern Tunisia. The ethnopharmacological uses of this specie in Tunisia are for treatment of inflammation. In fact, many people apply the powder of this species on the external inflamed area to reduce swelling and pain.

The present study provides a new insight into the organ architecture of *Teucrium ramosissimum* Desf. Biochemical compounds of *T. ramosissimum* leaves were detected using GC/MS apparatus. Histological analysis and enzyme levels showed that *T. ramosissimum* decreased LPS-mediated acute kidney injury by inhibiting tissues inflammation and reducing kidney tissue damage.

#### **2. Materials and methods**

#### **2.1 Chemicals**

*T. ramosissimum* essential oil solutions (100 mg/ml) were diluted in dimethyl sulfoxide for *in vivo* analysis. 5-Fluorouracil (5-FU) and LPS (*Escherichia coli* 055:B5) was obtained from Sigma-Aldrich Chemicals Co. (St. Louis, MO, USA).

Teucrium ramosissimum *Derived-Natural Products and Its Potent Effect in Alleviating… DOI: http://dx.doi.org/10.5772/intechopen.102788*

#### **2.2 Plant materials**

Leaves of *T. ramosissimum* were collected from the mount of Orbata (Gafsa, Tunisia) during the Springer (2018). Essential oil was extracted by Clevenger apparatus. Characterization of phytochemicals by GC-MS analysis indicated the presence of mono- and sesquiterpenic compounds.

#### **2.3 Analyses of oily fractions of** *T. ramosissimum* **with GC/MS**

Oily fractions (diluted in 10% hexane) were analysed using GC/MS on a model 6890 gas chromatograph with an autosampler coupled with an Agilent 5973 Mass Selective *Detector* (Agilent Technologies, Palo Alto, CA, USA) with an electron impact ionization of 70 eV. A Phenomenex capillary column, ZB-5MSi (30 m × 250 μm i.d., 0.5 μm film thickness) (Agilent Technologies, Hewlett-Packard, CA, USA) at a temperature rising from 40 to 280 °C (5 °C/min). The carrier gas at a purity of 99.999% used for GC/MS analyses was helium at a flow rate of 0.7 ml/min, a scan time of 1 s and mass range *m*/*z* 50–550. The terpenic compounds were identified by matching their retention indices with those of the Wiley 09 NIST 2011 mass spectral library of the apparatus.

#### **2.4 Protective effects of** *T. ramosissimum* **against LPS-induced renal inflammation**

#### *2.4.1 Experimental design*

Both sexes of Swiss albino mice (48, 25 g weight) were divided into 8 groups (n=6) and maintained in plastic cages (polypropylene). Mice, provided from Pasteur Animal Laboratory (Tunisia, Ethic# LNSP/Pro 152012), were housed under animal conditions (25 ± 5°C; 45–55 % relative humidity; 12 h light/dark cycles with free access to water and food.

Group 1: Normal control, orally treated with saline;

Group 2: negative control, orally treated with 10 μg/ml LPS;

Group 3: orally treated with 20 μg/kg *T. ramosissimum* essential oil diluted in Tween 80 (2%);

Group 4: orally treated with 50 μg/kg *T. ramosissimum* essential oil diluted in Tween 80 (2%);

Group 5: comparator control, orally treated with 20 mg/ kg/day 5-FU;

Group 6: orally treated with the mixture of LPS and *Teucrium* essential oil (10 μg/ml and 20 μg/kg, respectively);

Group 7: orally treated with the mixture of LPS and *Teucrium* essential oil (10 μg/ml and 50 μg/kg, respectively);

Group 8: orally treated with the mixture of LPS and 5-FU (10 μg/ml and 20 mg/kg, respectively).

Animals received drugs for one week. In the groups 6, 7 and 8, mice were treated with *Teucrium* essential oil or 5-FU 1 hour before LPS administration.

At the 8th day, mice were sacrificed and blood samples were collected by glass capillary tubes for plasma biomarker analysis. Kidney tissues were collected and processed for microscopic analysis.

#### **2.5 Statistical analyses**

Statistical analyses of *in vivo* study were performed using GraphPad Prism 4.00 to compare different groups with each other we used a two-way analysis of variance (ANOVA), followed by Tukey's multiple test. A value of *P* < 0.05 was considered statistically significant.

#### **3. Results and discussion**

#### **3.1 Ethnobotanical and phytochemical analysis of** *T. ramosissimum*

*T. ramosissimum* macromorphological features (nutlets, leaves, stems, flowers) are shown in **Figure 1**. The major phytocompounds were β-phellandrene, α-cadinol, T-Muurolol, α-bisabolol, camphor, endo-borneol, and epi-bicyclosesquiphellandrene (**Figure 2)**.

#### **3.2 Effects of** *T. ramosissimum* **on histological changes of cecum and serum biomarkers of the kidneys**

LPS mediated a significantly (*P*<0.05) increase in the levels of plasma urea, creatinine and uric acid (**Figure 3A**). The pretreatment of mice with *T. ramosissimum* notably reduced the levels of plasma biomarkers in serum. Macroscopic features of kidney taken from treated and untreated groups are shown in **Figure 3Bi**. As depicted in **Figure 3Bii**, normal glomerular histoarchitectural and numerous tubules was seen in the kidney and a significant increase in the tubular injury scores after LPS treatment, otherwise, we noted fibrotic lesions, leukocyte infiltration indicative of the inflammation within different areas in the glomeruli, and renal tubules degeneration associated to tubular epithelium desquamation, while no observed damage was detected in mice from normal control group. After one week of treatment of mice with LPS, pronounced tubular necrosis and kidney fibrotic scaring was observed in kidney, which was significantly reversed by *T. ramosissimum* treatment that improves significantly the renal functions when it was given prior to LPS administration (**Figure 3Biii**).

**Figure 1.** T. ramosissimum *plant. a: habitus; a: leaves; b,c: leaves; d,e: seeds.*

Teucrium ramosissimum *Derived-Natural Products and Its Potent Effect in Alleviating… DOI: http://dx.doi.org/10.5772/intechopen.102788*

#### **Figure 2.**

*Phytocompounds of* T. ramosissimum *essential oil isolated using GC/MS analysis.*

Free radicals- induced lipid peroxidation to be one of the major causes of cell membrane damage resulting in a series of pathological situations by causing acute and chronic renal injuries [10]. In fact, LPS is one of the most important causes of sepsis and is involved in the pathogenesis of SA-AKI, which may lead to "cytokine storm," intensified oxidative stress, low blood pressure, renal hypoperfusion, and finally a gradual decline in renal function [7]. In this report, photomicrograph overview revealed the potent protective effect of *T. ramosissimum* that could effectively attenuate the pathological cecum and renal alteration in LPS-induced colorectal inflammation and acute kidney injury in mice model by reducing inflammation. These imply that *T.ramosissimum* pretreatment may attenuates the pathological features of LPS-induced inflammation revealed by Hematoxylin & Eosin (H&E) staining.

#### **Figure 3.**

*A. Creatinine (i), urea (ii) and UA (iii) levels in plasma. B. Macroscopical view of mice kidney (i), histopathological analysis (ii) of kidney sections (scale bar = 250 μm) observed by H&E staining and Kidney tubular injury score (iii) of treated groups. Green arrows- inflammatory cell infiltration; red arrows: hemorage; blue arrows: edema of the intertubular spaces; TRs:* Teucrium ramosissimum*; G: glomerulus; dG: degenerated glomerulus. (H&E staining, Magnification: a–e ×40; f ×10). Data represent mean ± SD, n=6; \*\* P<0.01 vs. LPS.*

The current results further support previous findings on the effect of LPS to mediate tubule and glomerulus degeneration.

*T. ramosissimum* given prior to LPS treatment induced decrease in serum biomarkers (urea, uric acid, creatinine). In this report, plasma creatinine and urea increased significantly in LPS-treated group, and this indicate diminished ability of the kidneys to filter these waste products from the blood and excrete them in the urine [11]. Additionally, this work demonstrated that LPS increased uric acid that mediated arteriolopathy and interstitial inflammation suggest mechanisms that would exacerbate or potentiate progressive renal functional decline after injury. This process involves accumulation of free radicals. Moreover, in the kidney, LPS binds to TLR4 proteins and mediates the proinflammatory cytokines release, and more precisely IL-1β and TNF-α [7] and induces the transcriptional factor, NF-kB, activation that regulates a variety of inflammatory gene expression [12]. Effectively, any compound able to modulate inflammation or inflammation-related processes can be thought of as a renal protective agent and/or a potential treatment tool for controlling renal damage [13].

*T. ramosissimum* is traditionally used for the treatment of many diseases (inflammation, gastric ulcer, cancer). Its extracts markedly enhance cell proliferation either with or without mitogen (lipopolysaccharide [LPS] or lectin) stimulation and contain potent components such as flavonoids that may be potentially useful for modulating immune cell functions in physiological and pathological conditions. Moreover, *Teucrium* extract exert different protective effects against ethanol-induced ulcerogenesis [14]. Likewise, this species acts as chemopreventive and chemosensitizing agent against two uterine sarcoma cell lines, MES-SA and P-gp-overexpressing MES-SA/ Dx5 cells by a slight modulation of the cell cycle and its regulators, but also through a significant induction of apoptosis [15].

Teucrium ramosissimum *Derived-Natural Products and Its Potent Effect in Alleviating… DOI: http://dx.doi.org/10.5772/intechopen.102788*

#### **4. Conclusions**

This report affirms that phytpharmacological effects of *Teucrium* essential oil extracted at the flowering stage may be related to its derived products identified by GC/MS apparatus. *T. ramosissimum* can restore LPS-induced renal damage by inhibiting inflammation. The increase of serum biomarkers, together with glomerular and tubular alterations clearly indicate renal dysfunction.

#### **Acknowledgements**

The authors extend their appreciation to The Ministry of Higher Education and Scientific Research of Tunisia.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Fatma Guesmi\* and Ahmed Landoulsi Faculty of Sciences of Bizerte, Laboratory of Risks Related to Environmental Stresses: Fight and Prevention, University of Carthage, Carthage, Tunisia

\*Address all correspondence to: guesmif6@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[2] Napagoda M, Gerstmeier J, Butschek H, De Soyza S, Pace S, Lorenz S, et al. The anti-inflammatory and antimicrobial potential of selected ethnomedicinal plants from Sri Lanka. Molecules. 2020;**25**:1894. DOI: 10.3390/molecules 25081894

[3] Jarić S, Mitrović M, Pavlović P. Ethnobotanical features of *teucrium* species. In: Stanković M, editor. Teucrium Species: Biology and Applications. Cham: Springer; 2020. DOI: 10.1007/978-3-030-52159-2\_5

[4] Irshad M, Ali Subhani M, Ali S, Hussain A. Biological Importance of Essential Oils. Rijeka: Intechopen; 2019. DOI: 10.5772/intechopen.87198

[5] Fortrie G, de Geus HRH, Betjes MGH. The aftermath of acute kidney injury: A narrative review of long-term mortality and renal function. Critical Care. 2019;**23**:24. DOI: 10.1186/ s13054-019-2314-z

[6] Chawla LS, Bellomo R, Bihorac A, Goldstein SL, Siew ED, Bagshaw SM, et al. Acute kidney disease and renal recovery: Consensus report of the acute disease quality initiative (ADQI) 16 workgroup. Nature Reviews Nephrology. 2017;**13**:241-257

[7] Chen Y, Jin S, Teng X, Hu Z, Zhang Z, Qiu X, et al. Hydrogen sulfide attenuates LPS-induced acute kidney injury by inhibiting inflammation and oxidative

stress. Oxidative Medicine and Cellular Longevity. 2018;**2018**:10. DOI: 10.1155/2018/6717212

[8] Ben Sghaier M, Louhichi T, Ammari Y. Ethnobotanical and phytopharmacological notes on *teucrium ramosissimum* L. Research Review Biosciences. 2017;**12**(3):132

[9] Henchiri H, Bodo B, Deville A, Dubost L, Zourgui L, Raies A, et al. Sesquiterpenoids from *teucrium ramosissimum*. Phytochemistry. 2009;**70**(11-12):135-1441

[10] Farzaei MH, Zangeneh MM, Goodarzi N, Zangeneh A. Stereological assessment of nephroprotective effects of trachyspermum ammi essential oil against carbon tetrachlorideinduced nephrotoxicity in mice. International Journal of Morphology. 2018;**36**(2):750-757

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[12] Chunzhi G, Zunfeng L, Chengwei Q, Xiangmei B, Jingui Y. Hyperin protects against LPS-induced acute kidney injury by inhibiting TLR4 and NLRP3 signaling pathways. Oncotarget. 2016;**7**(50):82602-82608

[13] Avila-Carrasco L, García-Mayorga EA, Díaz-Avila DL, Garza-Veloz I, Martinez-Fierro ML, González-Mateo GT. Potential therapeutic effects of natural plant compounds in kidney disease. Molecules. 2021;**26**:6096. DOI: 10.3390/ molecules26206096

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[14] Ben Sghaier M, Harizi H, Louhichi T, Krifa M, Ghedira K, Chekir-Ghedira L. Anti-inflammatory and antiulcerogenic activities of leaf extracts and sesquiterpene from *teucrium ramosissimum* (Lamiaceae). Immunopharmacology and Immunotoxicology. 2011;**33**(4):656-662. DOI: 10.3109/08923973.2011.558903

[15] Lahmar A, Mathey A, Aires V, Elgueder D, Vejux A, Khlifi R, et al. Essential oils, *pituranthos chloranthus* and *teucrium ramosissimum*, chemosensitize resistant human uterine sarcoma MES-SA/Dx5 cells to doxorubicin by inducing apoptosis and targeting P-glycoprotein. Nutrients. 1719;**2021**:13. DOI: 10.3390/ nu13051719

#### **Chapter 10**

## Essential Oil, Chemical Compositions, and Therapeutic Potential

*Slimen Selmi, Kais Rtibi, Karim Hosni and Hichem Sebai*

#### **Abstract**

Essential oils-(EOs) are organic compounds derived from aromatic plant sources such as roots, bark, flowers, leaves and seeds. Essential oils were obtained via two different methods of extraction: steam distillation (SD) and water distillation (WD). EOs-therapy, refers to a range of traditional, alternative or complementary therapies that use essential oils from natural products and other aromatic plant compounds. The chemical components composition of EOs depends on the place of origin, climatic conditions, plant species, plant part extracted, and harvesting time. Essential oils are constituted by diversified bioactive constituents, lipophilic and volatile, and in most cases derivatives of terpene compounds and in lower occurrence phenylpropanoids. They have been long recognized for their medicinal uses: antiviral, antibacterial, insecticidal, antifungal, and antioxidant properties. This chapter provides studies on chemical composition, medicinal uses, and benefits of essential oils.

**Keywords:** essential oils, methods of extraction, bioactive chemical compositions, therapeutic potential

#### **1. Introduction**

Essential oils or vegetable essences are oily, volatile [1], odorous and colorless or slightly tinted products obtained by steam distillation, by expression, by incision or by enfleurage of the plant material [2]. These plant essences are widely distributed in the plant kingdom and exist only in higher plants. Indeed, they are found in appreciable quantity in approximately 2000 species divided into 60 botanical families such as for example in *Lamiaceae* (lavender, basil, mint …), *Myrtaceae* (eucalyptus), *Lauraceae* (cinnamon and sassafras), and the *Apiaceae* (coriander, cumin, fennel, parsley..) [3]. Essential oils are found in all the organs of the plant: roots, fruits, seeds, flowers, leaves, bark, wood, etc. They are formed in specialized cells, most often, grouped in channels or in secretory pockets and they are then transported to the different parts of the plant during its growth [4].

They differ from fatty oils, by their physical properties and their composition, because they volatilize on heat and their stains on the paper are transient [5]. They are characterized by their organoleptic properties (smell, color and taste). At room temperature, they are generally liquid with a density often lower than that of water. They are colorless or pale yellow, with a few exceptions such as the EOs of cinnamon (orange), wormwood (green) or chamomile (blue).

Their refractive index is high and most often they are endowed with rotary power. They are assigned different chemical indices (acid, ester, carbonyl number, etc.).

They are poorly soluble in water and soluble in organic solvents (ether, alcohol, hexane, pentane, etc.) [6]. They dissolve fats, iodine, sulfur, phosphorus and reduce certain salts. In addition, they oxidize and polymerize easily. To avoid this, they should be stored away from light and air.

People are beginning to use EOs widely for a variety of common conditions, and much research shows they may help relieve many disorders and their associated symptoms in some cases. The bioactive compounds in these oils may have several health benefits and actions on the human body and health. Very recent studies showed the use of these oils in many common health conditions such as anxiety, constipation, inflammation, depression and many other disruptions. The following chapter will provide more information on the novel method of extraction of EOs their chemical composition especially the main bioactive compounds, the medicinal uses, and their therapeutic benefits.

#### **2. Methods of extracting essential oils**

The extraction of essential oils from plant material can be carried out using many and various processes, based on ancient techniques:


#### **2.1 Distillation**

#### *2.1.1 Hydrodistillation*

It is the simplest and most widespread technique. It involves immersing the raw material directly in water, then the whole is brought to a boil. The operation is generally carried out at atmospheric pressure. The vapors formed are condensed by a water-flow refrigeration system.

**Figure 1.**

*Methods of extracting essential oils.*

#### *Essential Oil, Chemical Compositions, and Therapeutic Potential DOI: http://dx.doi.org/10.5772/intechopen.102447*

During the distillation of EOs, several phenomena are the basis of material exchanges between the solid, liquid and vapor phases, hence the influence of a large number of parameters on the quality and yield of the production of these plant essences [7].

Experiments carried out until the essence of the substrate is exhausted show that the duration of distillation is longer for the organs of woody plants than for herbaceous plants. This difference is strongly linked to the location of the production or storage systems for EOs, which are either on the surface or inside the tissues of the plant. As a result, these structures have an influence on the course of the hydrodistillation, that is to say on the successive mechanisms involved, and therefore on the duration of the extraction operation.

In the event that these structures are superficial, the outer membrane or the cuticle is quickly ruptured upon boiling, the volatile compounds are immediately evaporated. When EOs are subcutaneous, they must first diffuse through the thickness of the plant tissue before coming into contact with water or its vapor so that they can evaporate as in superficial secretions.

#### *2.1.2 Steam training*

In this type of distillation, a stream of water vapor passes through the plant which draws out the hydrophobic volatiles. After condensation, the separation takes place by settling. This method improves the quality of the EH by minimizing hydrolytic alterations.

#### *2.1.3 Distillation with organic solvents*

Some essential oils have a density close to water and the process by steam distillation cannot be used in this case. The principle consists of macerating the plant in the solvent in order to pass the odorous substances into the solvent.

#### *2.1.3.1 Petroleum based solvents*

This method uses organic solvents such as pentane, hexane, heptane, etc. It is reserved for EOs having a density close to that of water.

#### *2.1.3.2 Forane*

Forane 113 (F2CCl-CCl2F) extracts a mixture of H.E. and lipid oil at the same time, which makes it possible to double the plant.

#### *2.1.3.3 Carbon dioxide*

In liquid or supercritical carbon dioxide extraction, a stream of CO2 at high pressure burst gasoline pockets [8, 9]. This method is better than hydrodistillation in terms of cost, energy saving, yield and quality of the product obtained because the carbon dioxide is colorless, odorless, non-flammable and non-toxic.

#### **2.2 Microwave or ultrasonic assisted distillation**

These recent techniques offer several significant advantages over conventional techniques. In fact, they require a smaller volume of solvent and a reduced heating time, which prevents the loss and degradation of volatile and heat-sensitive compounds. Thus, they lead to higher returns [6, 10].

#### *2.2.1 Microwave extraction*

Microwave extraction involves heating the extractant (water or organic solvent) in contact with the plant under microwave energy which allows for homogeneous heating. This new extraction process saves considerable time and energy [11].

#### *2.2.2 Ultrasonic extraction*

The plant material brought into contact with the solvent (water or organic solvent) is immersed in a sonication bath maintained at constant agitation [12].

#### **2.3 Enfleurage**

The enfleurage is a rather difficult technique. It dates from ancient Egypt and is based on the strong affinity of odorous molecules for fats. It is mainly reserved for the fragile organs that are the flowers (violet, tuberose, jasmine, …). These are spread delicately on glass plates coated with a thin layer of grease and these plates are superimposed on wooden frames. Volatile substances diffuse and are absorbed by the fat layer. Then these facts are depleted with alcohol. This process tends to disappear because it requires a large workforce [13].

#### **2.4 Expression**

The expression or cold pressing is specific to the extraction of essential oils from citrus fruits: lemons, oranges, mandarins, etc. It is a fairly simple method which consists in mechanically breaking up by abrasion the gasoline pockets located at the level of the peel or pericarp of the fruit to collect its contents [14].

#### **2.5 Incision**

It is an infrequent operation. It is enough to split the bark of trees to collect the juice, for example the rubber of the rubber tree.

#### **3. Chemical composition of EOs**

The chemical composition of species is complex and can vary depending on the organism, climatic factors, the nature of the soil, cultivation practices and the method of extraction [15]. EOs are a mixture of constituents that belong to three categories of compounds: terpene, aromatic and various.

#### **3.1 Terpenes**

Terpenes are hydrocarbons formed by assembling two or more isoprene units. They are polymers of isoprene of the chemical formula (C5H8)n.

*Essential Oil, Chemical Compositions, and Therapeutic Potential DOI: http://dx.doi.org/10.5772/intechopen.102447*

Isoprene (2methylbuta-1,3-diene)

Depending on the number of associated units, a distinction is made between: mono- en (C10); sesqui- en (C15); di- en (C20); tri-en (C30); (C40) tetraterpenes and polyterpenes.

These units can bind to each other by so-called irregular bonds of the artemesyl, santolinyl, lavandulyl and chrysanthemyl type [16].

Essential oils contain particularly monoterpenes, sesquiterpenes and rarely diterpenes [17].

Terpenes have very diverse structures (acyclic, monocyclic, bicyclic, etc.) and contain most of the chemical functions of organic materials. As an indication, some structures of monoterpenes and sesquiterpenes are shown in **Figure 2**.

#### **3.2 Aromatic compounds**

The aromatic compounds are derived from phenylpropane (C6–C3). They are less common than terpenes. This class includes odorous compounds like vanillin, eugenol, anethole, estragole, … (**Figure 3**). They are frequently encountered in the EOs of Apiaceae (anise, fennel, parsley, etc.) and are characteristic of those of vanilla, tarragon, basil, cloves, etc. [6]. They differ from each other by:


#### **3.3 Compounds of various origins**

In general, low molecular weight compounds of various origins, which can be entrained during hydrodistillation, are straight or branched chain aliphatic hydrocarbons carrying different functions. As an indication, we can quote:

#### *Essential Oils - Advances in Extractions and Biological Applications*

**Figure 2.**

*Examples of mono- and sesquiterpene structures.*

**168 Figure 3.** *Examples of structures of compounds derived from phenylpropane.*

"The heptane and paraffin in chamomile oil;


#### **4. Properties of essential oils**

Essential oils have been used since ancient times for their most diverse therapeutic effects. The molecular diversity of the components they contain gives them very varied roles and biological properties [18].

In fact, monoterpene hydrocarbons have analgesic properties in percutaneous use, deworming, emmenagogue, atmospheric antiseptic, antiparasitic, etc. Sesquiterpene hydrocarbons have anti-inflammatory, calming, hypotensive effects [19].

The powers offered by the H.Es are innumerable and varied. It would be impossible to mention them all. The demonstration of their biological activity has been the subject of numerous studies [20].

#### **4.1 Role of essential oils in plants**

The biological role of H.Es in ecology is obvious. By their smell, they are involved in pollination. Thus, they play an attractive or repellent role with regard to predators (herbivores, insects, etc.) [7]. They can paralyze the masticatory muscles of attackers by the toxic and inappetent properties of the substances they contain [21].

They protect crops by inhibiting the multiplication of bacteria and fungi. They prevent the desiccation of the plant (loss of water) by excessive evaporation and protect the plant against light either by reduction or concentration.

Moreover, their compounds are involved in oxidation–reduction reactions, as hydrogen donors. For example, isoprene reacts rapidly with ozone and hydroxyl radicals. Also, they emit excess carbon and energy [22].

#### **4.2 Biological properties**

The spectrum of action of EOs is very wide, as they act against a wide range of bacteria, including those that develop resistance to antibiotics.

In addition, certain essences endowed with antifungal activity oppose the development of fungi and molds by destroying them [23]. These activities also vary from one essential oil to another and from one strain to another [24].

Essential oils act on both Gram-positive and Gram-negative bacteria. However, Gram-negative bacteria appear to be less sensitive to their action and this is directly linked to the structure of their cell wall [25] with some exceptions, such as Aeromonas hydrophila and Campylobacter jejuni, which have been described as particularly sensitive to the action of Essential oils [26]. Nevertheless, Pseudomonas aeruginosa, a Gram-negative bacterium, remains the least active vis-à-vis plant essences.

Aromatic molecules such as phenols followed by aldehydes then ketones then alcohols then ethers have the highest antibacterial coefficient. In general, the action of gasoline takes place in three distinct stages:


#### **4.3 Medicinal properties**

Essential oils have many and varied medicinal properties. Most of the constituents of essential oils have antimicrobial power, hence their use as antiseptics [27]. Others have digestive or antispasmodic, sedative, healing properties, etc. These activities are mainly due to their terpene constituents.

In addition, many EOs exhibit activity against all different types of pain and are widely used to treat inflammatory joint disorders. They have the property of strengthening and reviving the individual's immune defenses [28]. It is in this sense that we could say that aromatic essences were cytophylactic (protective of living cells).

In addition, some EOs have anti-tumor activities and are adopted in the preventive treatment of certain types of cancer (Nigella, Lemon balm) [29].

#### **5. Toxicity of essential oils**

EOs are powerful and very active substances. They represent an inexhaustible source of natural remedies. Nevertheless, it is important to emphasize that frequent and excessive self-medication, especially with regard to the dosage as well as the mode of internal or external application by the essences is harmful. It causes more or less harmful side effects in the body (allergies, coma, epilepsy, etc.) mainly in sensitive populations (children, pregnant and breastfeeding women, elderly or allergic people) [30].

The accumulation of essences in the body by repeated intakes can lead to nausea, headaches, etc. Ingestion of more than 10 mL of essential oil is neurotoxic and epileptogenic by inhibiting the supply of oxygen to the level in brain tissue [31].

#### **6. Main fields of application**

Due to their various properties, EOs have become a material of considerable economic importance with a constantly growing market. Indeed, they are marketed and are of great interest in various industrial sectors such as pharmaceuticals by their antiseptic, analgesic, antispasmodic, aperitif, anti-diabetic…, in food through their antioxidant activity and flavoring effect, in perfumery and cosmetics through their odoriferous property.

#### **6.1 Aromatherapy**

Aromatherapy is a form of alternative medicine in which EOs are of great importance because they induce many curative effects. Thus, they are used more and more in various medical specialties such as: chiropody, acupuncture, massage-physiotherapy, osteopathy, rheumatology as well as in esthetics [4].

#### **6.2 Food industry**

By virtue of their antiseptic and flavoring properties, EOs are used daily in culinary preparations (garlic, bay leaf, thyme, etc.). They are also very popular in liquorice (anise drinks, kümmel) and in confectionery (candies, chocolate, etc.). Their antioxidant power allows them to preserve food by avoiding mold, preserving smen for example with thyme and rosemary [32].

#### **6.3 Cosmetology and perfumery**

EOs are sought after in the perfume and cosmetics industry because of their odoriferous properties. The perfume industry consumes large tonnages of essences (60%) in particular those of rose, jasmine, violet, verbena, etc. EOs are also consumed in cosmetology to perfume cosmetic products: toothpastes, shampoos, sunscreens, lipsticks, soaps [33]. Hygiene products, detergents and laundry for example, also consume a lot of EO to mask the (often unpleasant) odors of pure products.

#### *6.3.1 Pharmacy*

Essences from plants are used largely in the preparation of infusion (mint, verbena, thyme, etc.) and in the form of galenic preparations. More than 40% of medicines are based on active plant components, for example gastralgin is an anti-acid digestive which consists of EO carvi [34].

Likewise, with their flavoring properties, they help mask the unpleasant odor of drugs taken orally. Also, many drugs sold in pharmacies are based on EOs such as eye drops, creams, elixirs [34].

### **7. Conclusion**

The current chapter discusses the diverse chemical bioactive compounds, the multifaceted applications of EOs in the therapeutic approach and develops its exciting potential as a novel green alternative to the toxic effects of synthetic agents. Being naturally used in food with rarely harmful actions and minimal adverse effects, EOs are exempted from toxicity aspects and accepted to be safe for preservation purposes. Also, they represent a considerable economic interest by their applications in the pharmaceutical, agro-food, cosmetological industries.

#### **Author details**

Slimen Selmi1 \*, Kais Rtibi1 , Karim Hosni2 and Hichem Sebai1

1 Laboratory Functional Physiology and Bio-resources Valorisation, Higher Institute of Biotechnology of Beja, University of Jendouba, Beja, Tunisia

2 Laboratory of Natural Substances, Institut National de Recherche et d'Analyse Physico-Chimique (INRAP), Technopole Sidi Thabet, Technological Pole, Ariana, Tunisia

\*Address all correspondence to: slimen.selmi@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 11**

## Essential Oils High in 1,8-Cineole of Mediterranean Flavoring Plants: Health Benefits

*Sílvia Macedo Arantes, Ana Teresa Caldeira and Maria Rosário Martins*

#### **Abstract**

Aromatic flavoring plants are important ingredients of the Mediterranean diet, one of the healthiest and most sustainable dietary forms, often associated with greater longevity as well as contributing to the reduction of some chronic pathologies with high mortality and morbidity. Their essential oils (EOs) are increasingly used as therapeutic agents and food supplements, due to their antioxidants, antiinflammatory or anti-tumoral properties. The Health benefits of essential oils are closely related with their chemical constituents. The 1,8-cineole, a naturally cyclic oxygenated monoterpene, has been attributed several biological properties such as antioxidants, anti-inflammatory or antitumoral. Nevertheless, the EO properties are attributed not only to their main components but also to the synergistic effect of minor components. This review chapter focused on the chemical composition and antioxidant and anti-inflammatory potential of EOs of flavoring Lamiaceae plants, with high content in 1,8-cineole, including chemotypes of genera *Lavandula*, *Calamintha*, *Rosmarinus,* and *Thymus*, often used in the Mediterranean diet.

**Keywords:** natural products, 1,8-cineole, antioxidants, anti-inflammatory properties

#### **1. Introduction**

Aromatic plants are increasingly used as therapeutic agents and as food supplements, along with industrial synthesis products. The World Health Organization (WHO) estimates that more than 80% of the world population uses products based on plant extracts and/or their active components for various purposes, including health care and phytotherapy [1–3].

Essential oils (EOs) are volatile compounds, products of secondary metabolic processes of aromatic plants and despite being practically insoluble in water, can be carried away by water vapor. They are largely obtained by water distillation or using steam distillation, from different parts of the plant, including the whole plant or just the wood, roots, leaves or flowers [4, 5]. Other processes to obtain oils from plants include expression, solvent extraction, CO2 extraction, maceration, cold pressure extraction [6]. Indeed, the species, the plant geographical conditions, and

the part of the plant used as well as the extraction method used will be determinants for the EOs chemical profile [7–11]. Otherwise, in the distillation process, thermal degradation of sensitive compounds, the photo-oxidation of light-sensitive compounds or the hydrolysis of esterified compounds are factors that can affect the chemical profile of EOs [7–12].

Aromatic, spice and medicinal plants are part of the Mediterranean diet, recognized by the WHO as a healthy and health-promoting type of diet [1, 2]. They also represent a growing interest in the food industry and are often used in alternative or complementary therapies in conventional medicine [13, 14]. Due to their effectiveness and, mainly, due to the lower number of adverse effects, when compared to synthetic drugs, the use of aromatic plants as functional foods as well their EOs may be an important role in the prevention of pathologies with high mortality and morbidity, such atherosclerosis, neurodegenerative diseases, diabetes, several infections, chronic inflammatory diseases, cancer and autoimmune diseases [15–20]. Some flavoring plants used in the Mediterranean diet are frequently used in Alentejo (South of Portugal) as food additives or flavors. Most of them belong to the Lamiaceae family and include *Lavandula* spp., *Calamintha* spp., *Rosmarinus* spp. and *Thymus* spp., in which EOs show chemical polymorphism with high content in 1,8-cineole and that are recognized for their antioxidant and anti-inflammatory potential [21–36].

The genus *Lavandula* comprises about 32 species, commonly known as lavender, such as *L. angustifolia and L. latifolia*, as well as Mediterranean *L. stoechas*, *L. pedunculata* and *L. viridis,* often found in the southern region of Portugal. Due to their great diversity, some species have a difficult taxonomic classification due to their hybridization capacity and morphological diversity, being important to characterize them by the composition of their OEs due to their great economic importance. *Lavandula* EOs are generally produced by distillation, either from the flower spike or from the leaves [37–39]. *Lavandula. stoechas* L. subsp. *luisieri* (Rozeira) Rozeira, *Lavandula pedunculata* (Mill.) Cav. and *Lavandula. viridis* L'Hér, are endemic to the Iberian Peninsula and wild growth in some regions the southern region of Portugal [40]. *L. luisieri* and *L. pedunculata* can be distinguished mainly by the shapes of the bracts the length of the stalks of the ears as well as by the diversity of their EOs components [21, 41, 42]. *L. viridis*, known as green lavender or white lavender, and their EOs showed antioxidant and anti-inflammatory activities, depending on the plant polymorphism and the EO chemotype [4, 21, 43–46].

The genus *Calamintha* consists of eight native species belonging to the Lamiaceae family, of which six species are extremely polymorphic [47]. *Calamintha nepeta* subsp. *nepeta* (syn. *Clinopodium nepeta* (L.) Kuntze) commonly known as neveda or calamint, is a perennial and quite aromatic plant and is widely distributed in the Mediterranean area [4, 40]. It is well known as a spice used in food flavoring and as an antiseptic and diuretic stimulant [48]. It is traditionally used in medicine as an antitussive and expectorant; it also has spasmolytic and anti-flatulence properties [49, 50]. Some studies report that its EO has antifungal and antibacterial activity, due to the high content of terpene derivatives [48]. It has also been reported that the EOs of this species have antioxidant, antimicrobial, anti-inflammatory and sedative properties [51–54].

The genus *Rosmarinus* (Lamiaceae) that grows wild in the western Mediterranean region is composed of three different species: *Rosmarinus officinalis*, *Rosmarinus eryocalix* and *Rosmarinus tomentosus* [55, 56]. *Rosmarinus officinalis* L. (Syn: *Salvia rosmarinus* Schleid and *Rosmarinus angustifolius* Mill) commonly known as rosemary is widely used worldwide and is indigenous from the Mediterranean region,

*Essential Oils High in 1,8-Cineole of Mediterranean Flavoring Plants: Health Benefits DOI: http://dx.doi.org/10.5772/intechopen.103831*

spontaneous in heaths, thickets and pine forests in the Center and South of the Continent [57–59]. Hepatoprotective, antioxidant and antimicrobial effects are attributed to this medicinal plant, as well as action in rheumatic diseases and digestive problems [59, 60].

The genus *Thymus* (Lamiaceae), also widely distributed in the Iberian Peninsula, is a taxonomically complex group of aromatic plants, traditionally used for medicinal purposes and contains about 214 species throughout the world [61–67]. *Thymus mastichina* (L.) is an endemic species of the Iberian Peninsula and it is found from north to south of Portugal (generally at the interior north and at the south) [4]. Commonly known as mastic thyme or Spanish marjoram, it is characterized by simple and opposite leaves and zygomorphic and bilabial flowers. *Thymus mastichina* L. subsp. *mastichina* has great ecological plasticity and is usually present in clearings of xerophytic bushes, roadsides, and slopes, abandoned fields, pine forests, cork oaks, stony areas and rocky outcrops. They prefer removed substrates, generally siliceous, quite sandy, and also schist and limestone substrates [68]. It is widely used for its medicinal properties, including antiseptic, digestive, antirheumatic, antispasmodic, expectorant and antitussive effects, and is also used as a flavoring plant in perfume and cosmetics industry [4, 68, 69]. *Thymus capitellatus* Hoffmanns & Link, commonly known as "*wild-thyme*", is an aromatic species endemic to the southern of Portugal, growing in sandy substrates of the Tagus and Sado basins (Extremadura, Ribatejo and Alentejo provinces of Iberian Peninsula) [70].

#### **2.** *Inter***- and** *intra***-specific differences in EOs compositions**

EOs are an important source of bioactive compounds with application in phytotherapy and traditional medicine. They are volatile complex compounds characterized by a strong odor and are rich in terpene compounds, namely monoterpenes (C10) and sesquiterpenes (C15), although diterpenes (C20) may also be present, as well as a variety of low molecular weight aliphatic hydrocarbons, acids, alcohols, aldehydes, acyclic esters or lactones and, exceptionally, compounds containing nitrogen (N) and sculpture (S), coumarins and phenylpropanoid homologs [6, 71, 72].

Among the different terpenes present in EOs, 1,8-cineole or eucalyptol (1,3,3 trimethyl-2-oxabicyclo [2.2.2] octane) in cyclic monoterpene oxide with a strong odor well known as the major constituent (>70%) of diverse eucalyptus species [73–78]. Some studies have demonstrated the high pharmacological potential of 1,8-cineole, namely as an antioxidant and anti-inflammatory compound [73–81]. With no negative effects in animal experiments, 1,8-cineole is considered safe when administered at normal doses (very high value of LD50 in rats - between 1.5 and 2.5 g/kg) [82]. Nevertheless, EOs of some Lamiaceae flavoring plants showed high content in 1,8-cineole, such as some lavenders (*Lavandula* ssp.) [21–23, 25, 42, 43, 45, 83–90], rosemary (*Rosmarinus officinalis*) [29, 30, 58, 91], *Calamintha nepeta* [26, 27, 50, 92, 93] and some *thymes* (*Thymus mastichina* [26, 27, 36, 94, 95] and *Thymus capitellatus* [70, 96]).

Due to their natural function, the chemical composition of EOs is determined not only by the genus, species, and subspecies of an aromatic plant but also by external factors such as geographic location, environmental conditions of the region, cultivation conditions, season and time of harvest [7–10]. In addition, it is also necessary to consider some procedures, such as techniques of plant collection or post-harvest conservation, part of the plant used, and the EOs extraction method also affects the chemical composition of EOs [7–10].

**Table 1** presents some of the main components of EOs of aromatic plants from the Mediterranean region of the genera *Lavandula*, *Calamintha*, *Rosmarinus* and *Thymus,* described in the bibliography. EOs of these flavoring plants present polymorphisms and, consequently, it is possible to find at least two or three chemotypes.

Some studies report that *L. luisieri* EOs has a unique composition in the Plantae kingdom, containing irregular cyclopentene monoterpenes derived from necrodane, such as α-necrodol, α-necrodyl acetate; in addition to, 1,8-cineole, lavandulyl acetate, α-pinene, linalool, camphor and fenchone [83, 86, 87, 97]. However, the chemical compositions of the EOs of *L. stoechas* subsp. *stoechas* and *L. stoechas* subsp. *luisieri* are quite distinct [85, 87], so this classification has been controversial studies carried out with the EOs of *L. luisieri* from southern Portugal, revealed a chemical profile rich in oxygenated monoterpenes (>50%) and hydrocarbons sesquiterpenes (5–11%), of which 1,8-cineole (18.8%), *trans-*α-necrodyl acetate (16.2%), lavandol (11.7%), *trans*-α-necrodol (10.6%), and *β-*caryophyllene (6.0%) [23]. Recently, a study with EOs of *L. luisieri* and *L. pedunculata* from Portugal reported EOs of *L. luisieri* with 1,8-cineole (6–34%); fenchone (0–18%) and α-Necrodyl acetate (3–17%); and *L. pedunculata* with major compounds 1,8-Cineole (12–34%); fenchone (6–50%) and camphor (10–34%) (three chemotypes: 1,8-cineole, fenchone and camphor) [88]. In studies carried out by Garcia-Vallejo*, et al.* [98] and Lavoine-Hanneguelle and Casabianca [87] with *L. luisieri* from Spain, the EOs presented as main compounds 1,8-cineole, lavandulol, lavandulyl acetate, linalool and their acetates, also present in other species of the genus *Lavandula*, in addition to some necrodane compounds. According to Miguel et al. [21] the populations of Spain showed high levels of 1,8-cineole, fenchone, camphor and necrodane derivates and, in the south of Portugal, the majority compound it was always the 1,8-cineole [84, 86].

EO of *L. pedunculata* showed high content of oxygenated monoterpenes, although with quantitative differences regarding the percentages of the various compounds [21, 90]. Studies carried out with *L. pedunculata* from central Portugal [90] indicate that its EO consists mainly of oxygenated monoterpenes (69–89%) and hydrocarbons monoterpenes (4.25–22.5%), with fenchone as the main constituents (1.3–59.7%), 1.8-cineole (2.4–55.5%) and camphor (3.6–48.0%). The EOs of *L. pedunculata* from central Portugal have been categorized into three chemotypes: 1,8-cineole, 1,8-cineole/camphor and fenchone [35], while the EO of *L. pedunculata* from the Algarve (Portugal) expresses the camphor/camphene chemotype [25].

Analysis of the EO of *L. viridis* revealed a chemical composition with a predominance of terpenoids, namely oxygenated monoterpenes (>50%) and hydrocarbons monoterpenes (>20%) and sesquiterpenes (<5%), presenting as majority: 1,8-cineole, camphor, α-pinene and linalool, the leaves of which are used, dried, in medical applications in Madeira, Portugal [43–46]. Some authors relate that the EO of the aerial part (leaf and flower) of this species contains mostly oxygenated monoterpenes (>50%), hydrocarbons monoterpenes (>20%) and sesquiterpenes (<5%), presenting as major compounds: 1,8-cineole (22–42%), camphor (2.9–31.5%), α-pinene (0.3–14.4%) and linalool (0.2–7.8%) [21, 43–45].

Depending on the variety and region, *Calamintha* EOs showed as major components carvacrol (45–65%), β-pinene, geraniol, α-caryophyllene and pulegone [48–50]. Previous studies with EOs oils from *C. nepeta* indicate the presence of a remarkable chemical polymorphism, suggesting the existence of two chemotypes: one characterized by the predominance of pulegone and menthone, menthol and/or its isomers, piperitenone, piperitone and their oxides [93, 99–105], and the other type characterized by the predominance of piperitenone oxide and/or piperitone oxide [93, 106]. Marongiu


*Essential Oils High in 1,8-Cineole of Mediterranean Flavoring Plants: Health Benefits DOI: http://dx.doi.org/10.5772/intechopen.103831*


*Essential Oils High in 1,8-Cineole of Mediterranean Flavoring Plants: Health Benefits DOI: http://dx.doi.org/10.5772/intechopen.103831*


#### **Table 1.**

*Main components present in some EOs of flavoring plants.*

*et al.* [50], in a study comparing the chemical profile carried out with Portuguese and Italian *C. nepeta*, reported that the EO of Portuguese *C. nepeta* presented as major components isomenthone, 1,8-cineole and isopulegone, while the Italian EO presented pulegone as a major component. Studies carried out with *C. nepeta* from southern Portugal reported that this EO had 1,8-cineole, isopulegol and isopulegone as major components [26]. Studies carried out with *C. nepeta* EOs from Alentejo (Portugal) have shown a peculiar chemical profile predominantly composed of isomenthone (35.8– 51.3%), 1,8-cineole (21.1–21.4%) and trans-isopulegone (7.8–6.0%) [27, 28, 107–109].

*Rosmarinus* EOs present α-pinene (up to 30%), β-pinene, camphene, limonene, myrcene, β-caryophyllene, cineole (15–30%), camphor (15–25%) as major compounds [4, 34]. The EO of *R. officinalis* presents a chemical polymorphism. In studies carried out by Ribeiro et al. [58], Wang et al. [29] and Boukhobza et al. [91] with the EO of *R. officinalis* from Portugal, China and Algeria, respectively, the EO presented as the majority compound 1,8-cineole. The EO of *R. officinalis* from Iran presented, as major components, α-pinene and linalool, with 14% each [30].

*Thymus vulgaris*, a flowering plant from genus *Thymus* and originating in southern Europe, is characterized by chemical component polymorphism according to the main volatile, with known six EOs chemotypes: geraniol, linalool, α-terpineol, tujanol-4, thymol and carvacrol [110]. *T. mastichina* is a related species to the *Thymus* genus but it presents a chemical polymorphism, with 1,8-cineole, limonene and β-terpinol as main constituents [4]. According to Salgueiro et al. [111], the EOs of some thyme species were characterized by a high content of 1.8-cineole and variable content of linalool, which varies with the geographical origin. Another study with EOs from *T. mastichina* reported 1,8-cineole (64%) as a major component, followed by α-terpineol (6%) and β-pinene (5%) [4, 112]. Moreover, Portuguese thyme from the *T. mastichina* section has also 1,8-cineole as the main constituent (often higher than 60%) [111]. Studies with a related species, *T. capitellatus* reveal the existence of polymorphisms in their EOs, reporting three chemotypes: the 1,8-cineole; the 1,8-cineole/borneol and the 1,8-cineole/linalyl acetate/linalool chemotypes [70].

#### **3. Health benefits of EOs**

Plants and their extracts have been used by mankind since the beginning of history and their secondary metabolites have traditionally played an important role in human health and well-being [71], increasingly important in therapeutics, due to their efficacy and, above all, due to the lower number of adverse effects when compared to synthetic drugs.

**Table 2** reports some pharmacological activities (antioxidant analgesic, antiinflammatory and cholinesterase inhibition) of EOs of some *Lavandula* spp., *Calamintha nepeta*, *Rosmarinus officinallis* and *Thymus mastichina* chemotypes high in 1,8-cineole. Depending on their chemical composition, either major and minor constituents, studies report antioxidant, antitumor, analgesic and anti-inflammatory, sedative or antispasmodic effects of these EOs [72, 113].

#### **3.1 Antioxidant activity of EOs**

The adverse effects of oxidative stress on human health have become a serious issue. This results from the imbalance between oxidant and antioxidant molecules, which can induce cellular damage by free radicals and promote the development of many current disease conditions, including inflammation, autoimmune diseases, cataracts, cancer, Parkinson's disease, arteriosclerosis and aging [1, 114]. Reactive oxygen species (ROS) are constantly generated and play important roles in a variety of normal biochemical functions as well as irregular or pathological processes. Furthermore, ROS can be produced by a family of mitochondrial membrane-bound enzymes, such as NAD(P)H oxidases, which appear to affect cell proliferation and apoptosis [115].

A broad definition of an antioxidant is "any substance which, present in low concentrations compared to that of the oxidizable substrate, effectively delays or inhibits the oxidation of that substrate". EOs are important antioxidants able to prevent or minimize the development of degenerative diseases, including cardiovascular diseases, cancer, neurodegenerative and inflammatory diseases [1].

Many of the medicinal plants belonging to the Lamiaceae family have antioxidant potential. Studies carried out with medicinal plants suggest that their antioxidant activity is due to the redox reactions of phenolic compounds, which allow them to act as reducing agents, donating hydrogen atoms and capturing singlet oxygen [116].

Some studies carried out with species of the genus *Lavandula* suggests that EOs from the aerial parts of these plants have antioxidant activity in protecting the lipid substrate and capturing free radicals, depending on their chemical constituents [21, 22, 37, 117, 118].


EOs of *C. nepeta* from Portugal have *in vitro* antioxidant capacity either to capture free radicals and to reduce Fe3+ or inhibit lipid oxidation [26–28]. Also, the EO of *R.* 

#### **Table 2.**

*Biological properties of EOs with high content in 1,8-cineole.*

#### *Essential Oils High in 1,8-Cineole of Mediterranean Flavoring Plants: Health Benefits DOI: http://dx.doi.org/10.5772/intechopen.103831*

*officinallis* with high content of 1,8-cineole reported that it could inhibit lipid peroxidation and capture free radicals [29, 31, 32, 34]. Studies carried out with *T. mastichina* EOs from Spain and Portugal showed that their EOs have shown low antioxidant activity by the DPPH radical method [26, 36, 119].

EOs are an important source of potentially useful antioxidants to prevent oxidative stress and promote human health [120]. According to the literature, the antioxidant activity of EOs is related to their high content of monoterpenes, namely limonene, 1,8-cineole, γ-terpinene, α-terpinene, linalool, 4-terpineol [60, 121, 122]. Additionally, the synergistic potential of minority constituents is often proposed to explain the differences between estimated and observed values for antioxidant capacities [123, 124]. Antioxidant properties of EOs also suggest their potential as anti-inflammatory agents, since the capture and elimination of free radicals is one of the mechanisms involved in the prevention of inflammation [125, 126]. Additionally, due to their high activity in protecting the lipid substrate, EOs have the potential to prevent neurodegenerative and cancerous diseases [35, 127].

#### **3.2 Anti-inflammatory activity of EOs**

The inflammatory response is one of the most important defense mechanisms of the body, responsible for removing and neutralizing invading microorganisms and/ or repairing tissues, involving, in its processes, immune cells of the hematopoietic system, such as macrophages. Cyclooxygenases (COX) play an important role in mediating the body's inflammatory response [128–130]. Cytokines released in the anti-inflammatory processes (IL-1, IL-2, IL-6, IL-8 and TNF or tumor necrosis factor) are also associated with other body responses, including immune and antiinflammatory responses or anti-tumoral and apoptosis processes [131–134].

EOs of several plants promote anti-inflammatory activity due to the presence of bioactive compounds such as oxygen monoterpenes that mediate the capture of free radicals generated by neutrophils and macrophages as well as for their ability to inhibit the cyclooxygenase pathway, having an important role in the regulation of inflammatory mediators [126, 135]. There is evidence that the association of chronic inflammation and oxidative stress with the aging process, indicating a subclinical chronic response. Additionally, the presence of reactive species in inflammatory processes are present in the etiology of several pathologies, including those resulting from metabolic disorders, demonstrating the central role of the reciprocal interaction between oxidative stress and inflammation [136–141].

The anti-inflammatory activity of EOs can be attributed not only to their antioxidant properties but also to interactions with signaling cascades involving cytokines and transcriptional regulatory factors and in the expression of pro-inflammatory genes [126, 142]. Some studies carried out in animal models with terpenes present in EOs, such as linalool, limonene, myrcene, 1,8-cineole, demonstrated that these compounds showed analgesic activity [143–152]. The analgesic and anti-inflammatory potential of OEs are preferentially attributed to the high content of terpene compounds [143, 145, 146, 153–156] as well as to the synergetic effect of minor components that can influence the pharmacokinetics and bioavailability of compounds with pharmacological action [157].

The anti-inflammatory effects observed for the EOs of *Lavandula* species can be attributed to their monoterpene content, namely 1,8-cineole, fenchone, linalool [143–147, 152]. For example, a study with EO from the leaves of *L. angustifolia*, high in 1,8-cineole (65%), borneol (12%) and camphor (10%) reported EO anti-inflammatory activity of 48% at a dose of 200 mg/kg [38]. In another case, Cardia et al. [158] demonstrated that the EO of *L. angustifolia* has anti-inflammatory activity by the method of paw edema induced by carrageenan, being able to inhibit, at a dose of 100 mg/kg, the inflammation in 54%, 56% or 45% after 30, 60 or 120 min, respectively. Recently, Zuzarte et al. [88] evaluated the anti-inflammatory activity of EOs of *L. luisieri* (high content in 1,8-cineole and fenchone and low quantities of necrodane derivatives) and three different EOs chemotypes of *L. pedunculata* (1,8-cineole, fenchone and camphor chemotypes) from Portugal and reported that EOs of *L. luisirei,* rich in 1,8-cineole and fenchone, was the EO with the highest anti-inflammatory potential and also was more active than its major compounds when assessed alone or in combination, confirming the synergetic effect of minor components.

Regarding the species of the genus *Thymus*, the most studied species is *T. vulgaris*, being widely recognized for the potential of its EOs and their major components as anti-inflammatory agents [159–161]. On the other hand, the literature reports that the monoterpenes 1,8-cineole, anethole and fenchone, major components present in the EOs of *C. nepeta* and *T. mastichina* may be also responsible for the anti-inflammatory effect [77, 143, 144, 147–152, 162].

#### **4. Conclusions**

EOs are increasingly used as therapeutic agents, cosmetics and food additives, along with industrial synthesis products, with application in phytotherapy. However, several factors can affect the biological properties of OEs, such as genera and species, time and region of harvest, extraction method, as well as the polymorphisms of each species. Correlation study between the biological properties of EOs and their chemical composition allows to evaluate its phytopharmaceutical potential and, together with traditional knowledge and practices, scientifically validate it, to allow an adequate, effective and safe use.

The biological activities of EOs are often related with its high content of some monoterpenes, such as 1,8-cineole which is an oxygenated monoterpene frequently found as one of the major components in the EOs of some plants of genera *Lavandula*, *Calamintha*, *Rosmarinus* and *Thymus*, autochthonous to the Mediterranean region. Several biological properties of EO of these plants have been attributed, including antioxidant (capacity to capture of free radicals or ability to protect the lipid substrate) and anti-inflammatory properties. These EOs properties are often attributed to their major components, however, the synergistic potential of minor constituents is often proposed to explain the differences between estimated and observed values.

#### **Acknowledgements**

This work was supported by the UIDB/04449/2020 and UIDP/04449/2020 projects, funded by Fundação para a Ciência e Tecnologia (FCT).

#### **Conflict of interest**

The authors declare no conflict of interest.

*Essential Oils High in 1,8-Cineole of Mediterranean Flavoring Plants: Health Benefits DOI: http://dx.doi.org/10.5772/intechopen.103831*

#### **Author details**

Sílvia Macedo Arantes1 , Ana Teresa Caldeira1,2,3 and Maria Rosário Martins1,4\*

1 Hercules Laboratory, Institute of Research and Advanced Training (IIFA), University of Evora, Evora, Portugal

2 Department of Chemistry and Biochemistry, School of Science and Technology, University of Evora, Evora, Portugal

3 City U Macau Chair in Sustainable Heritage, Institute of Research and Advanced Training (IIFA), University of Evora, Evora, Portugal

4 Department of Medical and Health Sciences, School of Health and Human Development, University of Evora, Evora, Portugal

\*Address all correspondence to: mrm@uevora.pt

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 12**

## Antioxidant Effect and Medicinal Properties of Allspice Essential Oil

*Yasvet Yareni Andrade Avila, Julián Cruz-Olivares and César Pérez-Alonso*

#### **Abstract**

*Pimenta dioica L. Merrill.* Myrtaceae family, known for its berries called pimenta or allspice, is one of the oldest spices in the world, widely used for its culinary and medicinal qualities. The main commercial product obtained from this spice is its essential oil, the reason for the interest in essential oil is based on the versatility of its use in different industrial areas (food, cosmetics, perfumery, and pharmaceuticals) due to its harmless and beneficial effects for health. In addition, it contains compounds that have shown broad biological activity, which turns out to be useful in the treatment of diseases related to the excessive formation of oxygen radicals. As a result, the extraction process and operating conditions have a significant impact on the bioactivity of these molecules. As a consequence, selecting the correct mix of variables to improve oil extraction and functionality is essential. The most of study on this essential oil is being focused on resolving these issues, as well as purification and identification. This chapter will cover the methods for obtaining *P. dioica* essential oil, as well as the chemical profile of the oil and its biological properties, which include its effects on humans, plants, animals, insects, and microorganisms.

**Keywords:** *Pimenta dioica*, essential oil, eugenol, antioxidant effect, chemical composition

#### **1. Introduction**

Allspice (*Pimenta dioica* L. Merrill or Pepper officinalis) belongs to the Myrtaceae family native to the West Indies and Central America [1]. In Mexico, it is found in the wild and is cultivated toward the east and southeast [2]. The commercial spice, known in Mexico as pimienta gorda and in English as "allspice," is a small tree that grows up to 6–12 m tall [3] with small, whitish flowers with a peculiar aroma; its dry, almost spherical, reddish-brown berries are the commercial pepper spice, known in Mexico as pimienta gorda; and in English as "allspice" for flavors that resemble a mixture of cinnamon, cloves, and nutmeg [4]. This spice is known for its antioxidant qualities, which are attributed to the presence of bioactive components, most especially polyphenolic compounds [5]. *P. dioica* is one of the most important spices as a source of essential oils high in eugenol, a phenolic compound having antibacterial and antioxidant properties against a variety of pathogens. *P. dioica* produced in Central

America is sent to the international markets because its use in the local market is minimal. Its manufacture and drying, on the other hand, are entirely traditional [6].

Allspice contains its oils both in its leaves and in the berry itself [7], with fairly variable returns (1.5–4.5%) [8]. According to reports, the oil content varies depending on where it originates located [9]. González and Pino [10] and Shaik et al. [11] also discovered that environmental parameters, harvesting procedures, drying, and the age of the trees all influence the chemical composition of the oil.

It is important to mention that the oil obtained from the leaf is a brownish-yellow liquid with a dry, woody, warm, and spicy aromatic smell, while the oil extracted from the berry is yellow in color with a warm spicy-sweet smell and a note of sweet and fresh output, and placed in the spicy-sweet and warm group [12].

Allspice essential oil is utilized in the food sector, specifically in the meat and tanner industries, and also in perfumery and cosmetic products [13]. In addition, it has been useful for the treatment of gastrointestinal disorders, cramps, flatulence, indigestion, and nausea. Likewise, it has managed to help in cases of depression, nervous exhaustion, tension, neuralgia, and stress, it is also used as a natural repellent [14]. Anesthetic, analgesic, antibacterial, antioxidant, antiseptic, acaricide, carminative, muscle relaxant, rubefacient, stimulant, and tonic are some of the medicinal effects of this essential oil [15].

The versatility of essential oils' use in different industrial areas (pharmaceuticals, food, and cosmetics) has sparked interest in recent years, not only because of the possibility of obtaining aromatic compounds, but also because of their use as antioxidants, food preservatives, and medicines, as well as their use as crop and plant protectants, incorporating them into the packaging material of the products [16].

#### **2. Essential oil extraction**

Steam distillation, hydrodistillation, and the use of organic solvents are the most common extraction procedures. To produce the essential oil, steam distillation uses saturated steam at atmospheric pressure. When the steam breaks the cells of the plant walls, the water generates steam, and the essence is freed, the extraction is complete [17, 18]. They allow the process to be favorable for the creation of alcohols and acids when the esters disintegrate by employing high temperatures and the presence of water, resulting in a decrease in the extraction of the oil, which is one of the limitations of distillation by steam entrainment [19].

In recent years, several novel techniques for extracting essential oils have been developed, including ultrasound-assisted extraction, microwave-assisted extraction, and extraction using supercritical fluids, with the goal of reducing extraction time, reducing solvent consumption, increasing extraction yield, and improving the quality of the extracts [20]. Traditional organic solvent extraction, while easy, has drawbacks, such as expensive prices, is not environmentally friendly, and is nonselective, requiring post-treatment processes for product purification. Nonrecyclable organic solvent disposal can also be hazardous to human health and the environment.

On the other hand, at the laboratory and pilot scale, supercritical fluid extraction of flavonoid compounds presents a viable alternative for a more efficient and environmentally friendly extraction process. The volatile concentrate obtained from allspice by supercritical fluids was compared to the oil obtained by the hydrodistillation method by Marongiu [21], with the primary differences being the amount of eugenol, 77.9% against 45.4%. It was also demonstrated that by employing supercritical CO2,

the extract has an additional benefit in that it is free of hydrocarbons, which can conceal or degrade the oil's natural aroma.

Other studies compared the effects of microwave energy supply and hydrodistillation radiation time (MHD) on the performance and composition of allspice essential oil [22]. While there were no significant differences in the yields (2.68% versus 3.25%) and chemical composition of essential oils obtained by HD and MHD, the advantage was obtained in the reduction of the extraction cost in terms of time and energy.

#### **3. Allspice essential oil chemical profile**

Polyphenols, lignins, and terpenoids are the most prevalent components found in allspice essential oil currently [23]. The basic component of the oil is eugenol, finding that the oil content obtained from the leaves (65–96%) is somewhat higher than that of the berry oil [14]. **Table 1** shows the chemical composition of the essential



#### **Table 1.**

*Chemical composition of the essential oil of* Pimenta dioica*.*

#### *Antioxidant Effect and Medicinal Properties of Allspice Essential Oil DOI: http://dx.doi.org/10.5772/intechopen.103001*

oil of *P. dioica* obtained by using gas chromatography coupled to mass spectrometry (GC-MS) analysis technique, as well as data from the literature obtained from various researchers denoting the main compounds present in the essential oil, according to the extraction method, geographical origin, and plant part used in the extraction. Essential oils are complicated combinations with a high number of elements, and their physicochemical qualities are controlled by factors, such as harvest time, soil type, and fruit storage conditions and time [24]. The quality of Jamaican berries is greater than that of other islands, and they are preferred for commerce. Allspice's oil content and flavor deteriorate when it is stored for an extended period of time [1].

Because of the extraction process used, the quantity and quality of compounds found vary. Essential oil composition has an important role in determining the spice's pharmacological potential [16]. The essential oil of *P. dioica* extracted using HD, SCD, SE, and SD have significant qualitative and quantitative changes in their chemical composition. Hydrodistillation was the most used procedure. Eugenol, methyl eugenol, and myrcene are the three main constituents of this oil.

#### **4. Antioxidant effect**

Spices and herbs are recognized as sources of natural antioxidants [46]. Some of the biological functions of essential oils are dependent on their antioxidant properties. These properties are attributable to some essential oil components' inherent potential to prevent or delay aerobic oxidation of organic matter. However, it is important to be cautious before thinking that essential oils' antioxidant properties are just a result of their chemical components. However, taking into account its composition can help to estimate its antioxidant capacity [47].

In terms of free radical scavenging activity against the radicals DPPH, ABTS, and superoxide anion, the composition and antioxidant activity of the essential oil obtained by hydrodistillation of the berries were studied [48]. A total of 45 components were discovered. Eugenol (74.71, 73.35%) was the most common component found, followed by methyl eugenol (4.08, 9.54%) and caryophyllene (4.08, 9.54%). The antioxidant evaluation revealed that the oil had a high rate of radical scavenging. The total phenolic content, total reducing power, and metal chelating capacity were also calculated, and the metal chelating capabilities and reducing power were both found to be extremely high. The essential oil has a substantial antioxidant activity that is comparable to pure eugenol, according to the results.

Another study showed a positive correlation between the anticancer and antioxidant effects of allspice essential oil [42]. As a member of the Myrtaceae family, this oil has been shown to have a great cytotoxic effect against cancer cells. As a result, it might be considered a natural source of anticancer medicines. According to research, consuming foods containing synthetic antioxidants can result in health problems, such as cancer owing to the accumulation of free radicals in the body. As a result, research has been done to return to using natural compounds as an alternative for synthetic substances and as a source of novel food preservatives. These essential oils with high inhibitory percentages can now be utilized to replace synthetic additives since they help to eliminate pollutants and chemical residues, which can cause issues and diseases [17].

Allspice is a powerful hydroxyl radical scavenger. The berries of *P. dioica* had a high level of antioxidant activity and scavenging activity for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical [49]. The capacity of *P. dioica* leaf essential oil to combat

DPPH (2,2-diphenyl-1-picrylhydrazyl), hydroxyl (OH), and superoxide radicals was studied to determine its antioxidant characteristics [33]. The intrinsic characteristics of many of their bioactive components, particularly phenols, to block or delay oxidation, are responsible for the antioxidant potential of *P. dioca* essential oil.

Although not all phenolic molecules had antibacterial activity, antioxidant activity was significantly related to total phenol content. *P. dioica* leaf extracts include phenolic chemicals that can be employed as antioxidants in the food, cosmetics, and pharmaceutical industries [50].

Allspice essential oil showed a high concentration of antioxidants The antioxidant characteristics of the essential oil were compared to those of propyl gallate, a synthetic antioxidant, and it was discovered that the essential oil's free radical scavenging activity was dependent on the concentration and higher than that of propyl gallate [51]. Antioxidants were found in abundance in allspice essential oil. (i.e. > 75 mmol/100 g) [52]. Applications in medicine have been reported due to the presence of antioxidant chemicals in *P. dioica*'s essential oil.

#### **5. Medicinal properties**

The essential oil of allspice is a significant source of phytochemicals in medicine. Phytochemicals are a large group of plant-derived bioactive that may have diseasefighting properties [53]. Plants are one of the most important natural sources of secondary metabolites for medical purposes, due to their biological capacity to combat lethal or endemic diseases, as well as disorders that impact living beings.

Anticancer, antidermatophytic, antihemorrhagic, anti-inflammatory, antimicrobial, antimutagenic, antipyretic, central nervous system depressant, hypoglycemic, hypotensive, an inhibitor of the enzyme histone acetyltransferase, and inhibitor of the enzyme histidine have all been discovered as pharmacological effects of allspice essential oil [54–57].

#### **5.1 Nematicidal activity**

In other studies, Park et al. [35] discovered allspice essential oil looks to be effective as a natural nematicide for B. xylophilus, but more research on systemic action, phytotoxicity, and formulation is needed to improve nematicidal potency and stability while reducing cost.

#### **5.2 Antimicrobial activity**

The presence of antioxidant properties and antimicrobial effects of allspice suggests that it can be used against human pathogenic bacteria and for the control of other diseases and the support of immunity for rejuvenation. The ability of allspice to alleviate bacterial infections and its use in traditional medicine in different parts of the world was observed. Due to its use, it is possible that this plant has anti-QS properties [58]. Its important bacteriostatic and inhibitory properties of pathogenic and decomposition microorganisms against *Bacillus subtilis*, *Clostridium botulinum*, *Escherichia coli*, *Listeria monocytogenes*, *Salmonella typhimurium*, and *Staphylococcus aureus* were also reported [59].

In another study, the essential oil extracted from *P. dioica* (Myrtaceae) was evaluated for its antimicrobial activities using a panel of gram-positive pathogens, gram-negative strains, and fungi [60]. Antimicrobial activity was measured by the minimum inhibitory concentration required to inhibit the growth of microorganisms. The cytotoxicity of the essential oil was tested *ex vivo* using the THP-1 macrophage cell model. The results showed that it had antimicrobial activity.

Allspice oil reduced xanthine oxidase activity, resulting in a decrease in superoxide radical formation. Both the synthesis of conjugated dienes and the development of secondary products from lipid peroxidation were effectively inhibited by allspice oil. Infections caused by *Klebsiella*, *Pseudomonas*, *A. niger*, *A. flavus*, and *T. versicolor* can be treated with *P. offcinalis* as an alternative to synthetic medications, according to the literature, depending on the chemical composition of the allspice oil [61]. Allspice has been shown to suppress *Escherichia coli*, *Salmonella enterica*, and *Listeria monocytogenes* [62].

The antibacterial activity of allspice essential oil was tested by using the agar diffusion method against three microorganism strains. *B. cereus*, *S. typhimurium*, and *S. aureus* were found to be inhibited by it. *B. cereus* was found to be the microbe most vulnerable to the presence of oil in the microdilution. The predominant component of *P. dioica* was eugenol, which had an abundance proportion of 94.86% as determined by GC-MS [41].

#### **5.3 Anticancer activity**

Cancer is a worldwide health issue. In breast (MCF-7), hepatocellular (HepG-2), colon (HCT-116), prostate (PC-3), and cervical cancer cell lines, allspice essential oil was examined for cytotoxicity. The MTT assay was used on HeLa cells. The essential oil had cytotoxic action against the cell lines that were examined [42]. The results showed that the essential oil of Mexican allspice has cytotoxic activity (IC50 < 15 μg/mL) against the cancer cell lines examined.

#### **5.4 Antifungal activity**

The antifungal efficacy of *P. dioica* leaf essential oil against toxin-producing Aspergillus flavus was investigated in one study. Antifungal activity of *P. dioica* leaf EO was shown on *A. flavus in vitro* experiments (IISRaf1). These tests revealed that this EO could be used as a food additive because of its antifungal properties and capacity to decrease ergosterol formation, which would extend the storage life of post-harvest items [63].

Allspice oil was found to have a superior antifungal impact against *Fusarium oxysporum*, *Fusarium verticillioides*, *Penicillium expansum*, *Penicillium brevicompactum*, *Aspergillus flavus*, and *Aspergillus fumigatus*. As a result, its efficacy is comparable to that of synthetic fungicides often used to treat severe human mycoses. The MIC values of *P. dioica*, which were detected against all pathogens tested, are very remarkable [64].

The fungal activity and chemical composition of the essential oil obtained from the fruits of *P. dioica* in the mycelial development of *Fusarium oxysporum* f. sp. *lycopersici*, *Fusarium oxysporum* f. sp. *passiflorae*, *Fusarium subglutinans* f. sp. *ananas*, *Fusarium oxysporum* f. sp. *vasinfectum*. The oil contained 76.88% eugenol and suppressed fungal mycelial development by up to 97.78% in an average of 7.2 days, according to the findings. As a result, the oil could be used as a natural fungicide [26].

*Aspergillus niger*, *Candida blanki*, *Candida tropicalis*, *Candida cylindracea*, *Saccharomyces cerevisiae*, and *Candida albicans* were found to have strong inhibitory activity, while *Candida glabrata*, *Candida krusei*, *C. albicans*, and *C. albicans* were found to have moderate inhibitory activity. With an activity index of 1.20–2.80, all of the test fungi were suppressed. This suggests that ketoconazole has a stronger antifungal effect against *C. albicans*, *Candida glabrata*, *C. tropicalis*, *Candida cylindracea*, *C. albicans*, and *Aspergillus niger* [65].

It has also recently become a research hub for the development of novel insecticides for ecologically friendly plants. Its insecticidal action has been demonstrated in numerous studies, and it can be utilized as a natural repellant [66].

#### **5.5 Antidiabetic effect**

Allspice berry extract was reported to inhibit protein glycation, indicating its potential to be used as an effective antidiabetic agent [67]. Studies have shown that individual flavonoids inhibit glycation by 50%.

#### **5.6 Acaricidal effect**

The essential oil derived from *P. dioica* berries was found to be highly harmful to *R. microplus* 10-day-old larvae in this investigation. As a result, the findings point to a viable new technique that could be utilized as an alternative to synthetic acaricides for tick management. The main components, methyl eugenol (62.7%) and eugenol (62.7%), could be responsible for acaricidal activity (8.3%) [39].

The active components of allspice essential oil were used in one investigation to cause mortality and limit the development of *B. microplus* to a level comparable to commercial acaricides. The phenylpropanoid molecules responsible for this activity, eugenol and methyl eugenol, could be studied for use as Acarina chemosterilants and as templates for the synthesis of further acaricides. All extracts, commercial acaricides, and methyl eugenol were found to be less effective in suppressing oviposition and causing tick mortality than berry essential oil. Eugenol, a component contained in more than 65% of the oil composition, is responsible for the effectiveness of berry essential oil [68].

#### **6. Conclusions**

Over the years, researchers have studied the enormous range of biological activities of allspice essential oil and its potential applications. *P. dioica* essential oil contains a large number of medicinal compounds. Currently, the need to extract compounds of interest from plant materials drives the continuous search for economically and ecologically viable extraction technologies. We have given a quick rundown of the medicinal characteristics of allspice essential oil, with a focus on the chemical components that have biological activity.

*Antioxidant Effect and Medicinal Properties of Allspice Essential Oil DOI: http://dx.doi.org/10.5772/intechopen.103001*

#### **Author details**

Yasvet Yareni Andrade Avila\*, Julián Cruz-Olivares and César Pérez-Alonso Facultad de Química, Universidad Autónoma del Estado de México, Toluca, Estado de México, Mexico

\*Address all correspondence to: yasvety@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Mozaniel Santana de Oliveira and Eloisa Helena de Aguiar Andrade*

Over the years, natural products such as essential oils have been gaining more and more prominence due to their perceived health benefits. Plants rich in essential oils represent a viable source of biomolecules for use in the most varied human activities, such as agricultural, cosmetic, and pharmaceutical applications. Essential oils are natural volatile fractions extracted from aromatic plants that are formed by classes of substances such as fatty acid esters, mono and sesquiterpenes, phenylpropanoids, and aldehyde alcohols, and in some cases, aliphatic hydrocarbons, among others. In this context, this book includes twelve chapters that present new information on the extraction and application of essential oils in various industrial segments. It is divided into three sections that discuss the general concepts of essential oils and techniques for their extraction, topics in food science and technology, and essential oils and their pharmacological properties in various activities and applications.

### *Miroslav Blumenberg, Biochemistry Series Editor*

Published in London, UK © 2022 IntechOpen © monsitj / iStock

Essential Oils - Advances in Extractions and Biological Applications

IntechOpen Series

Biochemistry, Volume 32

Essential Oils

Advances in Extractions

and Biological Applications

*Edited by Mozaniel Santana de Oliveira* 

*and Eloisa Helena de Aguiar Andrade*