**3. Antioxidant effects of melatonin**

Free radicals, which are low molecular weight, short-lived and unstable structures, are highly active chemical structures that have unpaired electrons in their final orbits and try to share the electrons of other compounds to make up for this gap [41, 42]. Free radicals, which cause oxidation, are mainly oxygen-derived metabolites, superoxide anions (O2 − ), hydrogen peroxide (H2O2), hydroxyl radical (OH− ), and lipid peroxides [43]. Oxidative stress occurs as a result of increased reactive oxygen species (ROS) for various reasons and insufficient antioxidant mechanisms. Free radicals, which are formed by natural metabolic pathways in the body, are normally eliminated by radical scavenging antioxidant systems. Antioxidants are the molecules that prevent cell damage by inhibiting the formation of free radicals or scavenging existing radicals [44, 45]. While antioxidants can be classified according to their structure as those being enzymatic [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and glutathione-S-transferase (GST)] and non-enzymatic [Reduced glutathione (GSH), vitamin A, vitamin C, vitamin E, and melatonin], they can also be classified according to their cell localization as (i) intracellular antioxidants (SOD, CAT, and GPx), (ii) extracellular antioxidants (albumin, vitamin C, and urate) and (iii) membrane antioxidants (vitamin A and vitamin E) [46].

Melatonin hormone, which is a non-enzyme antioxidant, helps to eliminate harmful conditions stimulated by oxidative stress by inhibiting protein oxidation, lipid peroxidation, mitochondrial damage, and DNA degradation due to both its direct free radical scavenging activity and its contribution to the antioxidant defense system [47]. Melatonin, which is an antioxidant and was first suggested in 1991 by Ianaş et al., keeps radicals before the membrane and detoxifies them by protecting the membrane by attaching them to the outer surface of the cell membrane [48]. Melatonin hormone removes hydroxyl and oxygen radicals and inhibits nitric oxide synthase [49] and this feature of melatonin [50] that prevents lipid peroxidation reactions, especially by scavenging the OH˙ radical, is due to the pyrrole ring in its structure [51]. Melatonin increases the levels of antioxidant enzymes, such as mitochondrial SOD, cytosolic SOD, GPx, and GSH in the cell [52]. In addition, it is a powerful antioxidant that prevents oxidative and nitrosative damage due to its ability to eliminate toxic oxygen derivatives formed in metabolic activities and reduces the formation of ROS and reactive nitrogen species [32, 53].

Melatonin shows its antioxidant effect in three ways. *(i) Direct antioxidant effect*: Blocking free radicals with the formation of N1-Acetyl-N2-formyl-5 methoxyquinuramine from the pyrrole ring of melatonin in the presence of free radicals [54–57], *(ii) Indirect antioxidant effect*: Suppressing oxidative stress by increasing the activity of enzymes, such as SOD, GPx, and GSH [54, 55], and *(iii) Effect via prooxidant enzyme*: Reducing free radical formation as a result of suppressing some prooxidant enzymes [48].

Antioxidant properties of melatonin have been shown in the studies conducted [58–62]. It has been reported that melatonin is at least two times more effective antioxidant than vitamin E and five times more effective than glutathione [55]. In the studies conducted, it is known that when melatonin is applied together with vitamin E and vitamin C, better protection is obtained than when applied alone [63] and melatonin has a suppressive effect on the formation of free radicals formed during electron transport in mitochondria. Melatonin reduces the formation of destructive toxic hydroxyl radicals by chelating transition metals taking place in Fenton/Haber-Weiss reactions [64]. It protects the biomolecules found in the whole structure of the

#### *Biochemistry and Antioxidant Effects of Melatonin DOI: http://dx.doi.org/10.5772/intechopen.106260*

cell against free radical formation by reacting with toxic hydroxyl radicals. Melatonin forms a non-enzymatic defense mechanism against the destructive properties of hydroxyl radicals and is more effective than other known antioxidants in protecting the organism against oxidative damage. It terminates lipid peroxidation by capturing the peroxide radical unlike antioxidants, such as ascorbic acid, alpha-tocopherol, and GSH. It has been reported that liver, kidney, and brain tissue glutathione peroxidase activity in rats increased after the administration of melatonin. Significant decreases in liver, lung, brain tissue, and glutathione peroxidase activity were reported in rats for which pinealectomy is made [48].

Many studies examining the effects on the synthesis and circulating amount of nitric oxide (NO), which is an important molecule of melatonin that plays a role in many physiological and physiopathological events, have been done. The physiological effect of NO occurs when soluble guanylate cyclase is activated to form cGMP. Decreased melatonin level causes decreased guanylate cyclase activity in many tissues. As a result, the cGMP level decreases, and the cAMP level increases. Thus, cell membrane thickness and rigidity increase, and degenerative damage formation accelerates [65]. When the relationship between NO and melatonin is examined, it has been suggested that the peroxynitrite anion, which is formed as a result of the reaction between NO and nitrosomelatonin and the reaction of NO and O2 in the presence of O2, is also occupied by melatonin [66, 67].

Unlike other antioxidants, it does not have a toxic effect in excessive use. Melatonin differs from classical antioxidants in various aspects and turns into less harmful pro-oxidant substances from the oxidants whose effects they abolish. However, after melatonin effects oxidant substances, is also effective as antioxidants in the intermediate stages and the resulting products. This property is very valuable as an antioxidant agent and is characterized as a "suicidal or terminal antioxidant" [68]. Melatonin reduces the synthesis of adhesion molecules and proinflammatory cytokines [69, 70]. Melatonin prevents linoleic acid, which is an energy source and growth factor of melatonin, which promotes the repair of damaged DNA, from entering the cell and suppresses its metabolism [71, 72].

### **4. Conclusion**

The shikimate pathway, used by bacteria, fungi, algae, and plants, is a seven-step metabolic pathway for the biosynthesis of aromatic amino acids. However, this pathway is absent in animals. For this reason, melatonin, a neurohormone synthesized from tryptophan, an essential amino acid that must be taken with food, is synthesized by the retina, bone marrow, and gastrointestinal system, mainly by the pineal gland. Melatonin plays a role in the regulation of many physiological and biological functions in animals, such as the regulation of sleep time, blood pressure, and breeding season. In addition, due to its small molecular size and high lipophilic, it can reach all organelles of the cell and cross the blood–brain barrier. In addition, melatonin, which is a powerful antioxidant, provides direct scavenging of hydroxyl and oxygen radicals with high toxicity and stimulates antioxidant enzymes.

*Melatonin - Recent Updates*
