**Abstract**

Current therapies for neurodegenerative diseases offer only limited benefits to their clinical symptoms and do not prevent the degeneration of neuronal cells. Neurological diseases affect millions of people around the world, and the economic impact of treatment is high, given that health care resources are scarce. Thus, many therapeutic strategies to delay or prevent neurodegeneration have been the subject of research for treatment. One strategy for this is the use of herbal and essential oils of different species of medicinal plants because they have several bioactive compounds and phytochemicals with neuroprotective capacity. In addition, they respond positively to neurological disorders, such as dementia, oxidative stress, anxiety, cerebral ischemia, and oxidative toxicity, suggesting their use as complementary treatment agents in the treatment of neurological disorders.

**Keywords:** neuroprotection, herbal medicines, neurological disorders, oxidative stress

## **1. Introduction**

A number of complementary treatment are currently being investigated to provide neuroprotection or to treat neurodegenerative diseases. Some therapies are known to provide limited benefits because, despite their treating the clinical symptoms, they are not effective in preventing neuronal cell degeneration.

The economic impact of treating neurodegenerative disorders is also high with disproportionately scarce neurological services and resources that patient survival may depend on. Studies have shown that over 80% of natural deaths in low- and

middle-income countries may be attributed to stroke [1]. In the United States alone, the combined annual costs of neurological diseases total nearly \$ 800 billion, expected to increase in the coming years due to an aging population, resulting in a severe economic burden to the health system [2].

Recent advances in understanding the pathophysiological mechanisms of neurological disorders have led to new strategies in drug development. Animal models have contributed considerably to these advances, as they play an important role in evaluating potential drugs that can alleviate these conditions and also delay their processes [3].

Interest in natural products has increased significantly, resulting in the increasing use of herbal medicines [4]. In a recent review, Izzo et al. report a 6.8% increase in US herbal and food supplement sales in 2014, with an estimated over \$ 6.4 billion in total sales [5].

The clinical and social repercussions of neuropathologies reveal an important theme of study and commitment to structure strategies that can contribute to the quality of life of society. Scientific research has explored which stimuli and substances can contribute to neural cell plasticity, resulting in improved quality of life for people with depression, Alzheimer's Disease (AD), Parkinson's Disease (PD), among other nervous system-related disorders [6].

Increased neurogenesis and the facilitating effects of plasticity can be produced by a variety of treatments, including enriched environment, physical activity or drug action [7]. A complementary treatment proposed is the use of herbal medicines, which have scientific relevance in the treatment of neurological diseases because they contain multiple compounds and phytochemicals that can have neuroprotective effect, with a consequent beneficial action for health in different neuropsychiatric and neurodegenerative disorders [8].

#### **2. Neuroprotective effect of extracts**

Studies have investigated therapies that can alleviate the symptoms of neurodegenerative disorders and also avoid the multiple pathogenic factors involved in these diseases. One promising approach is the use of herbal extracts and their isolated bioactive compounds for the treatment of conditions such as Parkinson's, Alzheimer's, cerebral ischemia. Behavioral analysis has shown them to have neurochemical activity and symptom reduction [9].

Recent advances in understanding the pathophysiological mechanisms related to neurodegenerative diseases point to new strategies in drug development [10]. Animal models have contributed considerably to these advances and play an even greater role in evaluating possible drugs with therapeutic potential, not only to alleviate these pathologies, but also to modify the disease process [3]. Rodents are suitable models for these studies because of their well-characterized brain organization and the magnitude of information focused on altered states of the nervous system [11, 12].

Phytotherapics have scientific relevance in the treatment of neurological diseases, as they contain multiple compounds and phytochemicals that can have neuroprotective effects, with consequent beneficial health action between different neuropsychiatric and neurodegenerative disorders [8–10]. Several extracts that have shown beneficial action in these disorders as will be addressed in this paper.

#### **2.1 Alzheimer's disease**

Alzheimer's disease (AD) is a neurodegenerative pathology that results in progressive loss of cell function, structure and number, leading to widespread brain

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*Extracts and Essential Oils from Medicinal Plants and Their Neuroprotective Effect*

atrophy and profound cognitive and behavioral deficit [13]. Histopathologically, it is characterized by accumulation of beta-amyloid peptide (ßA), which can initiate a cascade of oxidative events and chronic inflammation leading to neuro-

Several studies have investigated the action of *Piper methysticum* in experimental models of neurodegenerative diseases, specifically in AD, demonstrating the

*Piper methysticum* is popularly known as Kava or Kava-kava, a perennial shrub belonging to the Pacific Ocean pepper family (Piperaceae) with historical and cultural significance is described in the literature as a compound that has neuroprotective action and anxiolytic effects and is used in sedatives, and analgesics, being anti-inflammatory, anticonvulsant and anti-ischemic. Most of these pharmacological effects have been attributed to six kavalactones isolated from kava extracts, including yangonin, kawain and methysticin, dihydromethysticin, dihydrokavain

Recent studies, such as Fragoulis et al. have shown that one of the possible explanations for the action of piper mechanism in AD is associated with the activation of

Nrf2 is the major regulator of phase II detoxifying/antioxidant enzymes, including heme oxygenase 1 (HO-1). Transcription factor Nrf2 binds to ARE (antioxidant response element), transcribing a battery of genes involved in redox status, anti-inflammatory response and detoxification [19]. A study by Lobota et al. reports that Nrf2 activation and HO-1 induction are involved in the regulation of

Another study developed to find agents that activate the Nrf2 factor was performed and three analytically pure kavalactones - Methysticin, Yangonin and Kavain - were researched. The effects of kavalactones on the protection of neural cells against beta-amyloid peptide (ßA)-induced neurotoxicity were evaluated using the ARE-luciferase and Western blot assay. The results indicated that kavalactones Methysticin, Yangonin and Kavain activate time and dose-dependent Nrf2/ ARE in astroglial PC-12 and C6 neural C6 cells and thus up-regulate cytoprotective genes. At the same time, viability and cytotoxicity assays have shown that Nrf2 activation is able to protect neuronal cells from neurotoxicity by attenuating neuronal

Taken together, it is understood that the Nrf2/ARE signaling pathway is an attractive therapeutic target for neurodegenerative diseases and that chemically modified kavalactones as well as naturally occurring kavalactones can attenuate neurological damage by reducing oxidative stress and neuroinflammation.

Some herbal medicines have shown neuroprotective effects, such as curcumin, which is the main polyphenol found in turmeric (*Curcuma longa*), belonging to the Zingiberaceae family, native to South Asia and cultivated in the tropics [21]. It has been reported that this compound has properties that can prevent or ameliorate pathological processes related to neurodegenerative diseases such as cognitive decline, dementia and mood disorders [22]. In addition, curcumin has been investigated for experimental models of treatment for Parkinson's disease and has shown

Saffron compounds have been linked to beneficial biological properties such as anti-inflammatory, pro-apoptotic, antiproliferative, anti-amyloidogenic, antioxidant, antiviral, and antidiabetic [23, 24]. Saffron's most bioactive constituents are curcuminoids, including curcumin and its derivatives such as demethoxycurcumin

The features attributed to curcumin, such as inhibition of amyloid pathology, protection against inflammation and oxidative stress, inhibition of beta amyloid

*DOI: http://dx.doi.org/10.5772/intechopen.90903*

and desmethoxyyangonin [18].

cell death caused by β amyloid [14].

and bisdemetoxycurcumin [25, 26].

inflammation [20].

hopeful results [9].

neuroprotective effect of this herbal medicine [15–17].

the erythroid2-related nuclear factor (NrF2) [15].

nal death [14].

atrophy and profound cognitive and behavioral deficit [13]. Histopathologically, it is characterized by accumulation of beta-amyloid peptide (ßA), which can initiate a cascade of oxidative events and chronic inflammation leading to neuronal death [14].

Several studies have investigated the action of *Piper methysticum* in experimental models of neurodegenerative diseases, specifically in AD, demonstrating the neuroprotective effect of this herbal medicine [15–17].

*Piper methysticum* is popularly known as Kava or Kava-kava, a perennial shrub belonging to the Pacific Ocean pepper family (Piperaceae) with historical and cultural significance is described in the literature as a compound that has neuroprotective action and anxiolytic effects and is used in sedatives, and analgesics, being anti-inflammatory, anticonvulsant and anti-ischemic. Most of these pharmacological effects have been attributed to six kavalactones isolated from kava extracts, including yangonin, kawain and methysticin, dihydromethysticin, dihydrokavain and desmethoxyyangonin [18].

Recent studies, such as Fragoulis et al. have shown that one of the possible explanations for the action of piper mechanism in AD is associated with the activation of the erythroid2-related nuclear factor (NrF2) [15].

Nrf2 is the major regulator of phase II detoxifying/antioxidant enzymes, including heme oxygenase 1 (HO-1). Transcription factor Nrf2 binds to ARE (antioxidant response element), transcribing a battery of genes involved in redox status, anti-inflammatory response and detoxification [19]. A study by Lobota et al. reports that Nrf2 activation and HO-1 induction are involved in the regulation of inflammation [20].

Another study developed to find agents that activate the Nrf2 factor was performed and three analytically pure kavalactones - Methysticin, Yangonin and Kavain - were researched. The effects of kavalactones on the protection of neural cells against beta-amyloid peptide (ßA)-induced neurotoxicity were evaluated using the ARE-luciferase and Western blot assay. The results indicated that kavalactones Methysticin, Yangonin and Kavain activate time and dose-dependent Nrf2/ ARE in astroglial PC-12 and C6 neural C6 cells and thus up-regulate cytoprotective genes. At the same time, viability and cytotoxicity assays have shown that Nrf2 activation is able to protect neuronal cells from neurotoxicity by attenuating neuronal cell death caused by β amyloid [14].

Taken together, it is understood that the Nrf2/ARE signaling pathway is an attractive therapeutic target for neurodegenerative diseases and that chemically modified kavalactones as well as naturally occurring kavalactones can attenuate neurological damage by reducing oxidative stress and neuroinflammation.

Some herbal medicines have shown neuroprotective effects, such as curcumin, which is the main polyphenol found in turmeric (*Curcuma longa*), belonging to the Zingiberaceae family, native to South Asia and cultivated in the tropics [21]. It has been reported that this compound has properties that can prevent or ameliorate pathological processes related to neurodegenerative diseases such as cognitive decline, dementia and mood disorders [22]. In addition, curcumin has been investigated for experimental models of treatment for Parkinson's disease and has shown hopeful results [9].

Saffron compounds have been linked to beneficial biological properties such as anti-inflammatory, pro-apoptotic, antiproliferative, anti-amyloidogenic, antioxidant, antiviral, and antidiabetic [23, 24]. Saffron's most bioactive constituents are curcuminoids, including curcumin and its derivatives such as demethoxycurcumin and bisdemetoxycurcumin [25, 26].

The features attributed to curcumin, such as inhibition of amyloid pathology, protection against inflammation and oxidative stress, inhibition of beta amyloid

*Neuroprotection - New Approaches and Prospects*

processes [3].

in total sales [5].

severe economic burden to the health system [2].

among other nervous system-related disorders [6].

neuropsychiatric and neurodegenerative disorders [8].

**2. Neuroprotective effect of extracts**

chemical activity and symptom reduction [9].

middle-income countries may be attributed to stroke [1]. In the United States alone, the combined annual costs of neurological diseases total nearly \$ 800 billion, expected to increase in the coming years due to an aging population, resulting in a

Recent advances in understanding the pathophysiological mechanisms of neurological disorders have led to new strategies in drug development. Animal models have contributed considerably to these advances, as they play an important role in evaluating potential drugs that can alleviate these conditions and also delay their

Interest in natural products has increased significantly, resulting in the increasing use of herbal medicines [4]. In a recent review, Izzo et al. report a 6.8% increase in US herbal and food supplement sales in 2014, with an estimated over \$ 6.4 billion

The clinical and social repercussions of neuropathologies reveal an important theme of study and commitment to structure strategies that can contribute to the quality of life of society. Scientific research has explored which stimuli and substances can contribute to neural cell plasticity, resulting in improved quality of life for people with depression, Alzheimer's Disease (AD), Parkinson's Disease (PD),

Increased neurogenesis and the facilitating effects of plasticity can be produced by a variety of treatments, including enriched environment, physical activity or drug action [7]. A complementary treatment proposed is the use of herbal medicines, which have scientific relevance in the treatment of neurological diseases because they contain multiple compounds and phytochemicals that can have neuroprotective effect, with a consequent beneficial action for health in different

Studies have investigated therapies that can alleviate the symptoms of neurodegenerative disorders and also avoid the multiple pathogenic factors involved in these diseases. One promising approach is the use of herbal extracts and their isolated bioactive compounds for the treatment of conditions such as Parkinson's, Alzheimer's, cerebral ischemia. Behavioral analysis has shown them to have neuro-

Recent advances in understanding the pathophysiological mechanisms related to neurodegenerative diseases point to new strategies in drug development [10]. Animal models have contributed considerably to these advances and play an even greater role in evaluating possible drugs with therapeutic potential, not only to alleviate these pathologies, but also to modify the disease process [3]. Rodents are suitable models for these studies because of their well-characterized brain organization and the magnitude of information focused on altered states of the nervous system [11, 12]. Phytotherapics have scientific relevance in the treatment of neurological diseases, as they contain multiple compounds and phytochemicals that can have neuroprotective effects, with consequent beneficial health action between different neuropsychiatric and neurodegenerative disorders [8–10]. Several extracts that have

shown beneficial action in these disorders as will be addressed in this paper.

Alzheimer's disease (AD) is a neurodegenerative pathology that results in progressive loss of cell function, structure and number, leading to widespread brain

**70**

**2.1 Alzheimer's disease**

plaque aggregation and tau protein hyperphosphorylation, suggest that this compound may prevent or improve pathological processes related to cognitive decline and dementia, as occur in the symptomatology of AD patients [27, 28].

A systematic review study showed that curcumin has a positive action on AD symptoms, both when assessing biochemical and behavioral symptoms. The proposed mechanisms of its action in AD show that it is able to act by preventing the formation and aggregation of β-amyloid protein and tau protein hispanphosphorylation [10], in addition curcumin has also been shown to prevent neural damage, mitochondrial disorders, cellular stress and glial hyperactivation, as shown in **Figure 1**.

Another compound that represents a promising approach is *astragaloside IV* (AS-IV), a triterpenoid saponin present in the root of *Astragalus membranaceus* (Fisch.) Bge. It is part of Chinese traditional culture [29], first described in the Chinese book Shen Nong Ben Cao Jing in 200 AD with a number of beneficial effects and no toxicity.

The biological and pharmacological properties of AS-IV include its protective effect on pathologies due to its wide range of beneficial actions, such as antioxidant, antibacterial, antiviral [30, 31], anti-inflammatory, anti-asthmatic, antidiabetic, antifibrotic, immunoregulatory and antimicrobial, and cardioprotective effects, preventing myocardial insufficiency in rats [29–32], able to improve the immune system, digestion and promote wound healing [33].

Astragalus action can be understood based on the regulation of the release of caspases and cytochrome c (both being inducers of apoptosis), since cytochrome binds to Apaf-1 and Procaspase-9c when released into cytosol, forming a functional apoptosome and subsequently triggering the sequential activation of caspase-3 and 9 [34]. Several stimuli that induce apoptosis, leading to the release of mitochondrial cytochrome c which plays a key role in a common pathway of caspase activation [34, 35]. In addition, caspase-3 activation has been shown to be a fundamental step in the apoptosis process and its inhibition may block cellular apoptosis.

In addition, Chang et al. evaluated the action of AS-IV on the cerebral cortex after Aβ infusion, showing that i.p. Administration of 40 mg/kg/day of the herbal compound once daily for 14 days reduced the levels of mitochondrial dysfunction apoptosis in cortical cells blocked by inhibition of phosphoinositol 3-kinase (PI3K) protein kinase, known as AKT [36].

#### **Figure 1.**

*Active curcumin mechanisms after experimental treatment in AD models. Curcumin acts by preventing the formation and aggregation of β-amyloid protein and hyperphosphorylation of tau protein, stabilizing microtubules and preventing the formation of neurofibrillary tangles that occur due to deposition of this protein. It has also been shown to prevent mitochondrial damage favoring the increase of cellular ATP and the healthy maintenance of mitochondria, avoiding excessive Ca2+ intake. Curcumin is also able to counteract cellular stress and glial overactivation.*

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*Extracts and Essential Oils from Medicinal Plants and Their Neuroprotective Effect*

mentary treatment for the potential treatment of these pathologies [10].

pathology involves symptomatology related to both characteristics.

The beneficial effects of AS-IV administration in experimental models of neurodegenerative diseases proved to be effective in both in vivo and in vitro models, such as PD and AD, cerebral ischemia and encephalomyelitis by characterizing the antioxidant, antiapoptotic and anti-inflammatory action of this bioactive compound on the various neurochemical substances and behavioral mechanisms. This suggests that the mechanisms presented by AS-IV offer a possible future comple-

Parkinson's disease (PD) is a condition that causes progressive neurodegeneration of dopaminergic neurons with the consequent reduction of dopamine content in the substantia nigra. The 6-hydroxydopamine neurotoxin (6-OHDA) is widely

There are reports in the literature analyzing the effect of supplementation, including Chinese herbs and herbal extracts that have shown clinical potential to attenuate the progression of PD in humans. In addition, plant extracts act on the neurochemical or motor profile in isolation [38]. It is known, however, that this

A recently published systematic review study discussed studies showing neuroprotective properties of medicinal plants and their bioactive compounds. These included *Amburana cearenses* (Amburoside A), *Camellia sinensis* (Catechins and Polyphenols), *Gynostemma pentaphyllum* (Saponin Extract), *Pueraria lobata* (Puerarin), *Alpinia oxyphylla* (Protocatechuic Acid), *Cistanches salsa* (Glycosides

As previously mentioned, Astragaloside showed a neuroprotective effect on several AD models. In addition, studies have shown the positive action of AS-IV in PD models. One of the studies induced Parkinson by the action of 6-OHDA, where AS IV attenuated the loss of dopaminergic neurons and the treated group presented intact germination, neurite growth and increased immunoreactive TH and NOS. In addition, when the pathology was induced in SH-SY5Y cell culture by MPP + (DP inducing drug) action, it also significantly reversed cell loss, nuclear condensation, intracellular generation of reactive oxygen species and pathway inhibitio*n as m*ediated by Bax; these effects, however, were related only to neurochemical analysis.

One legume that has become the target of scientific research for its neuroprotective properties is *Mucuna pruriens*. Behavioral analysis studies have been carried out with *Mucuna pruriens* (Alkaloids, coumarins, flavonoids, triterpenes, saponins, carotenoids) and Baicalein (Flavonoids) for PD, but no neurochemical evaluation has been performed. There are also publications demonstrating in vivo behavioral effects and in vitro neurochemical analyses, such as a recent publication showing the effect of *Ligusticum officinale* (Makino) on MPTP (1-methyl-4-phenyl-1,2,3,6) induced with an animal model and tetrahydropyridine, a neurotoxin capable of permanently causing symptoms of Parkinson's disease by destroying the dopaminergic neurons of the substantia nigra. This drug has been used to study the disease in experiments with animals; the treatment restored behavior when compared to the control group. In this study, *Withania somnifera* (Ashwagandha) extract also

showed improvement in all these physiological anomalies [9, 40–43].

Another study investigated the ability of guanosine to protect neuronal PC12 cells from toxicity induced by 1-methyl-4-phenylpyridinium (MPP), the active metabolite of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), which mediates selective damage to dopaminergic neurons and causes irreversible

or Phenylethanoids), *Spirulina platensis* (Polysaccharide), and *Astragalus* 

*Membranaceus* - AS IV Tetracillic Saponin Triterpenoid [9].

Behavioral findings were not reported [39].

*DOI: http://dx.doi.org/10.5772/intechopen.90903*

used to mimic the neuropathology of PD [37].

**2.2 Parkinson's disease**

The beneficial effects of AS-IV administration in experimental models of neurodegenerative diseases proved to be effective in both in vivo and in vitro models, such as PD and AD, cerebral ischemia and encephalomyelitis by characterizing the antioxidant, antiapoptotic and anti-inflammatory action of this bioactive compound on the various neurochemical substances and behavioral mechanisms. This suggests that the mechanisms presented by AS-IV offer a possible future complementary treatment for the potential treatment of these pathologies [10].
