Melatonin Hormone As A Therapeutic Weapon Against Neurodegenerative Diseases

Abstract: Brain disorders such as Alzheimer’s and Parkinson’s disease (PD) are irreversible conditions with several cognitive problems, including learning disabilities, memory loss, movement abnormalities, and speech problems. These disorders are caused by various factors, mainly due to the toxic pollutants-induced biochemical changes in protein production, uncontrolled neuronal electrical activity, and altered neurotransmitter levels. Oxidative stress and toxicity associated with the increased glutamate levels decreased acetylcholine levels, and brain inflammation is the main contributing factor. Melatonin hormone is considered one of the potent treatment approaches for neurodegenerative disorders. 

Click to check Cistanche tubulosa memory extract

Melatonin is released from the pineal gland and is critical to brain function regulation. Membrane receptors, binding sites, and chemical interaction mediate hormonal actions having multiple phenotypic expressions. It acts as a neurodegenerative agent against some neurological disorders such as Alzheimer’s disease (AD), PD, depression, and migraines. Melatonin inhibits neurotoxic pollutants-induced Tau protein hyperphosphorylation, especially in AD. Other pivotal features of melatonin are its anti-inflammatory properties, which decrease pro-inflammatory cytokines expression and factors such as IL-8, IL-6, and TNF. Melatonin also reduces NO (an inflammation factor). In this review, we have highlighted the protective effects of melatonin, mainly spotlighting its neuroprotective mechanisms that will be beneficial in assessing its effects in environmental pollution-induced neurodegenerative pathology. 

Keywords: Alzheimer’s disease; Inflammation; Melatonin; Parkinson’s disease; Neurodegenerative agent

Introduction 

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects 2% of the elderly populace worldwide (1). Amyloid plaques and filamentous sheaths with brain amyloid angiopathy are two major symptoms in AD patients. The imbalance between beta-amyloid (Aβ) synthesis from amyloid precursor protein and its brain clearance is the main cause of Aβ accumulation and its pathogenicity (2). Intracellular Aβ assemblages destroy the endolysosomal-autophagic system and subsequent synthesis of autophagic vacuole and malformed mitochondria in the neuron (3). There are significant interactions between Aβ and Tau proteins, which are the major microtubule-associated protein of a mature neuron that binds to microtubules and stabilizes the whole microtubule network (4). Beta-amyloid assemblages inside and outside the neurons. 

On the other hand, intra-neuronal hyperphosphorylated Tau, dendritic spines analysis, and synapse degradation may eventually lead to memory losses in AD-affected people. Amyloid plaques are identified in the early stage of AD in the cortex and hippocampus as they spread from the pre-clinical stage to the clinical stage, propagated in the central nervous system or CNS (5). Glia-associated inflammations and neuronal deaths in AD decrease neuronal functions and consequently cognitive impairments (6). Parkinson’s disease (PD) is another neurodegenerative disorder that affects about 1.8% of elderly people. It is caused by the progressive losses of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the mid-brain and a successive loss of dopamine and clinically manifested by defective motor functions, reduced cognitive functions, and depression. Biochemical analyses suggested that reactive oxygen species (ROS) or reactive nitrogen species (RNS) are pivotal mediators in PD. The disease occasionally has genetic links, and signs, and symptoms of PD likely develop, at least in part, after free radical damage to the SNpc. Additionally, the inflammation of neurons and malfunctioning of mitochondria contribute to the etiology of this disease and enhance oxidative damage to the dopaminergic neuronal population. 

Once a large percentage of these cells are lost, PD signs appear (7). Melatonin (N-acetyl-5-methoxy tryptamine) hormone is released from the midbrain pineal gland and some peripheral tissues. This hormone is one of the G-protein coupled receptors family, activating intracellular signaling pathways (8). Melatonin, a tryptophan metabolite, has several physiological roles such as circadian rhythms regulation, free radicals scavenging, immunity enhancement, and generally inhibiting biomolecule oxidation (9). This hormone has a protective effect on neurodegenerative disorders (10). Reduction in the melatonin serum level and cerebrospinal fluid (CSF), and a decrease in daily melatonin are reported in AD patients. 

Further, melatonin levels in CSF decrease after developing AD neuron-based pathologies (11). Melatonin content in CSF and human post-mortem glands is decreased with the first symptoms of AD neuropathology (12). There is a potent association between pineal content, CSF, and plasma melatonin levels, which may be an early marker in AD's early stages (13). Other features of AD can be characterized by synaptic degradation, neurites or neuronal degeneration, endosome aggregation, lysosomes, and abnormal mitochondria (such as extracorporeal aneurysms). Synapses deterioration and neuron apoptosis in the limbic system cause cognitive deficits in AD patients (Figure 1) (14). Melatonin diversity functions can be recognized as the fact that melatonin receptors are located in numerous tissues (15). Brain melatonin receptors can be seen in the prefrontal cortex, cerebellum, hippocampus, basal nucleus, substantia nigra, nucleus accumbens, retina, and also in various hypothalamus cells. 

Moreover, these receptors are revealed in peripheral tissues such as the gastrointestinal tract, adipose tissue, pancreas, ovary, skin, lung, heart, and lymphocytes (16). Melatonin has two general class receptors, which include G-family receptors [(melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2)] and quinone reductase [melatonin receptor 3 (MT3)] enzyme family. The MT1 and MT2 can initiate cell signaling pathways after binding to their ligand, each of which leads to a specific response (15, 16). Down-regulated immunity via MT2 and increased immunity via MT1 have been reported in the AD patients’ hippocampus (17). MT1 and MT2 are unique receptors with distinguished pharmacological characteristics and chromosomal localization. MT1 and MT2 receptors are 350 and 362 amino acids in length, respectively, with molecular masses of 39–40 kDa (18). 

These receptors signal by coupling with heterotrimeric Gi protein which contains α, β, and γ subunits. Activation of these receptors promotes the dissociation of G proteins into α, β, and γ dimers which interact with downstream cell signaling molecules (19). Downstream molecules in MT1 and MT2 receptors signaling by G protein coupling involve adenylyl cyclase, phospholipase C, phospholipase A2, potassium channels, guanylyl cyclase, and calcium channels (20). Tissues enriched with MT1 and MT2 receptors include the retina, brain, suprachiasmatic nucleus, pars tuberalis, ovaries, kidney, pancreas, adipocytes, and immune cells (21). Other properties that consider melatonin a protective factor against many diseases such as cancer or neurodegenerative diseases are its anti-apoptotic properties. 

Although melatonin anti-apoptotic signaling pathways have not yet been fully identified, it has been shown that melatonin can be activated by some protective pathways, such as increased Bcl-xL, Bcl-2, super oxidase dismutase, and glutathione peroxidase, or scavenging of free radicals (22). Inhibition of some factors involved in apoptosis such as caspase, decreased MAPK, and ERK activity prevented the increase of the Rip process in cells to comfort protection against apoptosis (23). Many studies have shown melatonin effects on AD, cerebrovascular diseases, Amyotrophic Lateral Sclerosis (ALS), and PD. Studies found that the occurrence of these diseases is usually accompanied by a loss of melatonin or its receptors (24). Other melatonin functions comprise anti-inflammatory properties. 

Melatonin can affect many inflammatory factors such as NO and NOS (25). This hormone regulates cytokines synthesis such as IL-6, IL-8, and other inflammatory parameters. Melatonin slows down certain disease progression (26). El-Shenawy et al. (25) observed the anti-apoptotic effect of melatonin on neurodegenerative diseases. Melatonin can be used to reduce Huntington's symptoms (27). Moreover, in vitro melatonin has been unraveled to counteract ALS, Parkinson’s, stroke, and AD pathways wherein melatonin prevents mitochondrial-dependent apoptotic pathways both in vitro and in vivo and interferes with cell survival (28).

Effect of environmental factors 

Numerous environmental pollutants have been shown to mediate neurodegeneration through alterations in Tau phosphorylation, aggregation of proteins such as α-synuclein (α-syn), mitochondrial dysfunction, and alterations in metal homeostasis (29). Studies have revealed that Aβ42 and cyclooxygenase 2 (neuroinflammation indicator) levels are higher in the hippocampus and frontal cortex of persons exposed to high air pollution (30). Air pollutants activate microglia and the generation of pro-inflammatory cytokines which led to ventriculomegaly (through toxicity to oligodendrocytes) and hypomyelination (30). Previous in vivo studies on the Tg2576 mice showed that the acute subcutaneous administration of organophosphate pesticide chlorpyrifos (50 mg/kg) increased memory loss and Aβ levels in the hippocampus and cortex and reduced motor activity after 6 months (31). 

Although nanoparticles are promising therapeutic tools for neurodegenerative disease, some evidence associating them with alteration of the molecular mechanisms was involved in the pathogenesis of the neurodegenerative disease (32). Ze et al (33) showed that the nasal administration of 2.5–10 mg/kg TiO2 nanoparticles for 90 days caused oxidative stress, cell death in the hippocampus, and a decline in cognition and memory-associated genes. Also, a reduction in electrophysiological endpoints and spatial cognition was found in another study on rats exposed to 0.5 mg/kg CuO-NPs (14 days, i.p.) that conformed by a high level of ROS formation and lipid peroxidation and decreased antioxidants enzymes level (34). Numerous experimental and epidemiological studies emphasized the potential risk of exposure to environmental pollutants including nanoparticles, pesticides, metals, and the development of neurodegenerative diseases (35). Due to similar toxicity mechanisms based on the reduced levels of antioxidant enzymes and oxidative stress generation by these pollutants, natural antioxidants including melatonin, curcumin, resveratrol, etc, and their nanoformulations have gained more attention (35-37).

Melatonin induces improvement in neurodegenerative diseases 

Numerous studies revealed the effect of melatonin on AD. Improved memory in Alzheimer's mice and in vitro reduction in beta-amyloid apoptosis by melatonin was studied (27). In another study, melatonin was able to prevent Tau protein hyperphosphorylation by inhibiting cAMP, reducing PKA activity, and reducing CREB phosphorylation in vitro (38). Melatonin has strong anti-inflammatory properties, which suppress pro-inflammatory cytokines and factors such as IL-8, IL-6, and TNF expression (39). Since melatonin is one of the best antioxidant agents as it directly scavenges free radicals, it is used in remarkably large numbers of experimental models in which the pathogenicity is thought to be mediated by free radicals in one way or another (7, 40). 

Also, melatonin reduces NO (an important factor involved in inflammation. Furthermore, according to Tan et al. (41) AFMK metabolism, which has melatonin-like abilities, was higher in meningitis patients than in normal individuals. Korkmaz et al. (42) also reported that melatonin inhibited inflammatory enzyme activation (Figure 2). Melatonin decreases nitrate by reducing iNOS in PSLPS / IFN U by inhibiting NFkB activity. Melatonin can also show a protective effect in traumatic CNS defects (43). According to Hong et al. (44) in the chronic SCI (Spinal Cord Injury) model, melatonin reduced secondary injury and accelerated recovery by inhibiting lipid peroxidation induced by neutrophils.

Effect of melatonin on Akt/ Protein Kinase (PKB) B Pathway 

This pathway is a cell survival key mediator and apoptotic stimuli factor. PI3K /Akt pathway has the main role in nerve cell survival (45). When PI3K is activated membrane phospholipids produce phosphatidylinositol, which in turn induces Akt phosphorylation, succeeding that factors such as Bcl-2 are activated and inhibiting apoptosis (46). These proteins are anti-apoptotic. Eliminating 2-Bcl endogenous nerve signals directly comforts neuron apoptosis in neurodegenerative diseases. JNK pathway prevents apoptosis in neurodegenerative disease (47). Melatonin suppresses apoptosis by affecting cellular signaling and downregulates the apoptosis process. During neurodegenerative disease progression, signaling cascades are mediated by neuronal protection factors including the phospho-inositol 3 kinase activator pathway and N-kinase 3 protein kinase (48).

Effect of melatonin on decreasing Aβ toxicity 

Aβ molecule (39−43 amino acids), a derivative form of amyloid precursor protein (APP), has a fundamental function in AD. APP is a member of the amyloid precursor protein family APLP1 and APLP2. All of these proteins pass through the membrane at one time and have a large outer membrane region. All members of this family can produce amyloid fragments and mRNA down-regulation levels by APP, leading to isoform production, which is the most common form in the nervous system (49, 50). The 695 amino acid variants of APP are predominantly in the CNS, but 751 and 770 amino acid variants are expressed elsewhere. Similar studies revealed potential properties for Aβ, which can be activated by kinetic enzymes in oxidative stress regulation (51). 

Melatonin's anti-fibrillogenic effects have been unraveled by various microscopic and spectroscopic techniques (52). Further, the reaction between melatonin and Aβ has been assumed to be associated with structure and melatonin properties (53). Studies from spectrometric techniques have identified that melatonin interacts with about 40 amino acid residues of Aβ, especially aspartate, and histidine, which are favorable to forming β-sheet. Breaking these bonds results in the Aβ molecule's dissolution. Melatonin interaction with succinate imidazolecarboxylate bridges led to β-sheet structure conversion into random coils. Thus melatonin not only prevents the β-sheet formation and reduces neurotoxicity but also reduces Aβ peptide secretion through increased proteolytic degradation (54). 

Aβ molecule's over-expression led to cellular damage including lipid peroxidation, increased intracellular free calcium concentration, mitochondrial DNA oxidative damage, and released apoptosis indicators. Studies have shown that melatonin regulates mitochondrial internal membrane fluidity and binds to the mitochondrial membrane. Suppression of Aβ aggregation is considered the main factor in AD treatment. Recently, various types of research have shown that melatonin can react with Aβ40 and Aβ42 molecules to prevent their gradual progression to β-sheet or amyloid fiber (Table 1) (54, 55).

Melatonin suppresses Tau proteins synthesis 

Tau is the leading protein found in the axon which stabilizes neural pathways, microtubules, and neural transmission. This gene is located on chromosome 17 long arm and contains 16 exons (56). Tau is present not only in neuron axons but also in oligodendrocytes. Tau hyperphosphorylated form is not soluble, in which its propensity to microtubules is reduced and spontaneously forms complex interconnected structures (57). Tau proteins accumulate outside of AD and other CNS diseases (39). These types of disorders are known as Tauopathy. The amount of neurofibrillary strings is one of the AD prognosis markers (58). The main components of these coils are hyperphosphorylated and accumulated Tau protein forms. 

Like Aβ oligomers, abnormal Tau protein intermediate aggregates also have deleterious effects on cells and cause cognitive impairment. Insoluble complex strands may have no adverse effect but decreased synaptic transmission and neuron numbers are due to neurofibrillary coils’ detrimental effects. Parkinson's disease has identified more than 30 mutations in the tau gene on chromosome 17 (59). In contrast, there is no mutation in Tau protein in AD, and neurofibrillary coil formation is not a result of Tau protein mutation. However, an increase in the amount of Tau phosphorylation in cerebrospinal fluid is directly related to a decrease in cognitive test scores. 

Increased levels of Tau phosphorylated in cerebrospinal fluid can be administrated as a proper biomarker in predicting and diagnosing AD early stages in cognitive impairment patients. Melatonin synthesis inhibition caused spatial memory impairments in mice and elevated Tau phosphorylation via PP-2A activity suppression (60). Melatonin supplementation with 5-hydroxyindoleO-methyltransferase significantly increased memory retention arrested Tau, and reduced hyperphosphorylation, oxidative stresses, and PP-2A activities (60).

Protective effect of melatonin on neuroinflammation 

In some species, pinealectomy and other experimental processes which inhibit the melatonin secretions stimulate the immunosuppression stage which is further reversed by administrating the melatonin (61). In various in vivo experimental models and in vitro studies, melatonin induces inflammatory cytokines and nitric oxide synthesis. Melatonin induces T-lymphocytes, monocytes, natural killer cells, granulocytes, cell-dependent cytotoxicities, and antibodies-dependent response (62). In addition, NF-κB DNA binding inhibition by melatonin significantly reduces pro-inflammatory response and leads to a 50% reduction of Aβ-induced pro-inflammatory cytokines. However, T-lymphocyte and NK cells are of immense interest in neural inflammation. Melatonin has an anti-inflammatory effect via targeting IL-6, IL-2, IL-1b, IL-12, IL-1, TNF-α, and IFN-β cytokines (63). 

Melatonin in monocytes increases ROS formation and cellular toxicity, indicating the dual effects of melatonin on inflammation (64). Although, its effect on the synthesis of monocytes and microglial cells has not been reported. Melatonin has significant effects on lymphocyte number alteration and other leukocytes in peripheral immune system tissues. However, these changes in the immune system during adolescence may have an adverse health effect and indirectly affect CNS. Further, melatonin directs the inhibition of prostaglandin E2 (PGE2) on IL-2 synthesis. It upregulates anti-inflammatory factors L-10 and IL-2 (65). 

These two anti-inflammatory effects of melatonin in macrophages are mediated by the kB-NF pathway, which involves cyclo oxidase 2 (COX 2) expression through iOS activation. Reports have revealed that melatonin inhibits apical apoptosis and DNA fragmentation by inhibiting caspase-1 activity and IL-1β secretion in brain cells. It also prevents inflammation through Akt / K-PI3, JNK, and Akt phosphorylation pathways. Melatonin regulates apoptotic signals by downregulating phosphorylation / MEK1, 1-Raf, and ERK1, thereby preventing cellular damage (66).

Melatonin as free radicals scavenger 

ATP is produced in the mitochondrial electron transfer chain during cellular respiration. In normal conditions, 5.5% of oxygen is changed into approximately one species of oxygen (67). The maximum amount of ROS radicals are superoxide anion (O2) which is composed of an electron origin of oxygen (O2) molecule. Other low-cost ROS compounds containing anion nitrite peroxide are hydroxyl radicals, carbonate radicals, and nitrogen dioxide (NO2) which are synthesized by defective cellular components and have deleterious effects on protein synthesis (67). Henceforth, free radical scavenging has a key role in many neurological, immune disorders, and inflammatory, and mitochondrial diseases. 

Incomplete mitochondrial function is one of the most effective causes of free-radicals species in diseases such as neurodegenerative diseases, ischemia, and the aging process. Hence, increased free radicals, respiratory activity, mitochondrial production activity, and defects in the electron transport chain are causing mitochondrial dysfunction and cellular death. Melatonin induces glutathione synthesis, another antioxidant that decreases mitochondrial electron chain electron emission (68). 

Melatonin is selectively absorbed by mitochondria and acts as a potent antioxidative agent and regulates mitochondria's bioenergetic functions (69). It increases mitochondrial membrane permeability and stimulates disparate antioxidant enzymes. Hence, melatonin can resist oxidative damage by repairing microsomal membranes. Melatonin reduces free radical production. It prevents electron emission over the long term and thus improves mitochondrial function by inhibiting electron charging. The highest level of melatonin is found in mitochondria (70).

Role of melatonin in PD treatment 

PD is a neurological disorder in which dopaminergic cells damage the substantia nigra and striatum. Several research reports emphasized mutation, oxidative stresses, and free radical-induced increment in mitochondrial and dopamine-metabolizing enzymes (74). Therefore, antioxidants administration has been recommended as a promising therapy for PD (75). Singhal et al. (76) used neurotoxin (MPTP) in the rat PD model and found a melatonin-induced reduction in MPTP-mediated lipid peroxidation and hypertriglyceridemia. Within the last decade, hundreds of reports present scientific data for the therapeutic roles of melatonin in several OS-related disorders with the protective actions being attributed to the direct and indirect antioxidant traits of indole. Melatonin is being used in several experimental models in which the pathogeny is thought to be mediated by free radicals in one way or another.

The primary proof of a special relevance between melatonin and PD came from findings of decreased pineal activities and successive reductions in circulating melatonin concentrations in PD-affected people (40). Melatonin also increases antioxidant enzyme levels, besides the prevention of apoptosis in the hippocampus. This preventive mechanism of melatonin involves the inhibition of extracellular calcium exchange through the mitochondrial membrane, stimulating the mtPTP pathway, avoiding ROS formation, and cytochrome C secretion reducing. Another study in the mice animal model indicated that melatonin inhibited caspase-3 activity. MPTP exerts its neurodegenerative effects by increasing NO synthesis, which led to dopaminergic fiber impairment in the striatum nerve end. 

Melatonin acts through the JNK pathway to prevent dopaminergic apoptosis in substantia nigra and striatum and thus, it downregulates iNOS and NO levels in nerve cells and influences this process (77). Melatonin also stimulates Mn-SOD, antioxidant, and GPx antioxidants in dopaminergic cells (78, 79). Further, melatonin increases mitochondrial complexes 1 and 3 activity and has beneficial effects. It preserves mitochondrial homeostasis, reduces free radicals synthesis, and improves ATP synthesis. Therefore, melatonin may prevent apoptotic cascade and dedopaminergic neuron apoptosis (80). Contrary to the above, a few studies have revealed that abnormal aggregation of the cytoskeleton affects neurodegenerative disease pathogenesis. Levi's bodies, which are cytopathological markers of PD, are abnormal structures of tubulin, ubiquitin, and microtubule proteins 1 and 2. 

Melatonin is very effective in the formation and regeneration of the cytoskeleton formation and hence, it is possible to be one of the potential therapeutic molecules in neurodegenerative diseases. Various studies have revealed that melatonin has a potent curative significance as a neuroprotective agent in PD, ALS, and brain trauma. Moreover, melatonin clinical trials established its neuroprotective effects (81). Recent studies showed the improved therapeutic potential of melatonin using biological origin nanocarriers for drug delivery (82). These nanoformulations could provide high effectiveness in crossing the blood-brain barriers and extending melatonin release (82, 83). The distinguishing features enable melatonin to protect neurodegeneration by targeting mitochondrial-related pathways (84). Of course, it should be noted that attention to other factors such as genetic issues, gene therapy, and genetic diversity in this regard is very important (85-87).

Conclusion 

Melatonin is an endogenous, non-toxic, and antioxidative agent. It is considered a beneficial agent in different neurodegenerative disorders including AD and PD as a co-treatment with conventional therapeutic methods. Various studies on melatonin suggest that it can be used as a supplement in neurodegenerative disorders through its multiple effects, especially anti-apoptotic and anti-inflammatory properties. The experimental data collectively suggested that melatonin use would reduce their disease burden. Because neural diseases are generally caused by oxidative damage, melatonin has been investigated in varied experimental models. Melatonin-based therapy seems to be an ideal approach to reducing cognitive impairments in AD and PD-affected elderly people.

Why eating Cistanche can treat AD&PD

Cistanche contains bioactive compounds that have been found to have neuroprotective effects. Specifically, it contains echinacoside and acteoside which have been shown to improve cognitive function and protect against neurodegeneration in animal studies. These compounds have also been found to have anti-inflammatory and antioxidant properties which can help to reduce damage to brain cells and improve brain health. Additionally, Cistanche has been found to increase levels of neurotransmitters such as dopamine and acetylcholine which are important for maintaining brain function and are depleted in AD and PD. 

References 

1 Bush AI. The metallobiology of Alzheimer's disease. Trends Neurosci 2003; 26(4): 207-214. 

2. Kepp KP. Alzheimer’s disease due to loss of function: A new synthesis of the available data. Prog Neurobiol 2016; 143: 36-60. 

3. Poirier J. Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease. Neurobiol Aging 2005; 26(3): 355- 361. 

4. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21(3): 383-421. 

5. Holscher C. Development of beta-amyloid-induced neurodegeneration in Alzheimer's disease and novel neuroprotective strategies. Rev Neurosci 2005; 16(3): 181. 

6. Andersen JV, Christensen SK, Westi EW, Diaz-delCastillo M, Tanila H, Schousboe A, et al. Deficient astrocyte metabolism impairs glutamine synthesis and neurotransmitter homeostasis in a mouse model of Alzheimer's disease. Neurobiol Dis 2021; 148: 105198. 

7. Mayo JC, Sainz RM, Tan D-X, Antolín I, Rodríguez C, Reiter RJ. Melatonin and Parkinson’s disease. Endocr 2005; 27(2): 169- 178. 

8. Pohanka M. Alzheimer's disease and related neurodegenerative disorders: implication and counteracting of melatonin. J Appl Biomed 2011; 9(4): 185-196. 

9. Skene DJ, Swaab DF. Melatonin rhythmicity: effect of age and Alzheimer's disease. Exp Gerontol 2003; 38(1-2): 199-206. 

10. Rudnitskaya EA, Maksimova KY, Muraleva NA, Logvinov SV, Yanshole LV, Kolosova NG et al. Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease. Biogerontology 2015; 16(3): 303-316. 

11. Jean-Louis G, Zizi F, Von Gizycki H, Taub H. Effects of melatonin in two individuals with Alzheimer's disease. Percept Mot Skills 1998; 87(1): 331-339. 

12. Matsubara E, Bryant‐Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D et al. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease. J Neurochem 2003; 85(5): 1101-1108. 

13. Mihardja M, Roy J, Wong KY, Aquili L, Heng BC, Chan YS, et al. Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer's disease. Ann N Y Acad Sci 2020; 1478(1): 43-62. 

14. Brunner P, Sözer-Topcular N, Jockers R, Ravid R, Angeloni D, Fraschini F et al. Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer's disease. European J Histochem 2006; 50(4): 311-316. 

15. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 2008; 85(3): 335-353. 

16. Ng KY, Leong MK, Liang H, Paxinos G. Melatonin receptors: distribution in the mammalian brain and their respective putative functions. Brain Struct Funct 2017; 222(7): 2921-2939. 

17. Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother 2006; 60(3): 97-108. 

18. Krause DN, Dubocovich ML. Melatonin receptors. Annu Rev Pharmacol Toxicol 1991; 31(1): 549-568. 19. Dubocovich ML, Markowska M. Functional MT 1 and MT 2 melatonin receptors in mammals. Endocr 2005; 27(2): 101-110. 

20. Jockers R, Maurice P, Boutin J, Delagrange P. Melatonin receptors, heterodimerization, signal transduction, and binding sites: what's new? Br J Pharmacol 2008; 154(6): 1182-1195. 

21. Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML et al. MT2 melatonin receptors are present and functional in rat caudal arteries. J Pharmacol Exp Ther 2002; 302(3): 1295-1302. 

22. He H, Dong W, Huang F. Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer's disease. Curr Neuropharmacol 2010; 8(3): 211-217. 

23. Wongprayoon P, Govitrapong P. Melatonin as a mitochondrial protector in neurodegenerative diseases. Cell Mol Life Sci 2017; 74(21): 3999-4014. 

24. Andrabi SA, Sayeed I, Siemen D, Wolf G, Horn TF. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti‐apoptotic effects of melatonin. The FASEB J 2004; 18(7): 869-871. 

25. El-Shenawy SM, Abdel-Salam OM, Baiuomy AR, El-Batran S, Arbid MS. Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Pharmacol Res 2002; 46(3): 235-243. 

26. Samiei M, Ahmadian E, Eftekhari A, Eghbal MA, Rezaie F, Vinken M. Cell junctions and oral health. EXCLI J 2019; 18: 317. 

27. Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González‐Gallego J. A review of the molecular aspects of melatonin’s anti‐inflammatory actions: recent insights and new perspectives. J Pineal Res 2013; 54(1): 1-14. 

28. Cardinali DP, Pagano ES, Bernasconi PAS, Reynoso R, Scacchi P. Melatonin and mitochondrial dysfunction in the central nervous system. Horm Behav 2013; 63(2): 322-330. 

29. Ventriglio A, Bellomo A, di Gioia I, Di Sabatino D, Favale D, De Berardis D et al. Environmental pollution and mental health: a narrative review of the literature. CNS Spectr 2021; 26(1): 51-61. 

30. Allen JL, Oberdorster G, Morris-Schaffer K, Wong C, Klocke C, Sobolewski M et al. Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders. Neurotoxicol 2017; 59: 140-154. 

31. G Salazar J, Ribes D, Cabre M, L Domingo J, Sanchez-Santed F, Teresa Colomina MJ. Amyloid β peptide levels increase in the brain of AβPP Swedish mice after exposure to chlorpyrifos. Curr Alzheimer Res 2011; 8(7): 732-740. 

32. Hussain Z, Thu HE, Elsayed I, Abourehab MA, Khan S, So hail M et al. Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and prospects. J Control Release 2020; 328: 873-894 

33. Ze Y, Hu R, Wang X, Sang X, Ze X, Li B et al. Neurotoxicity and gene‐expressed profile in brain‐injured mice caused by exposure to titanium dioxide nanoparticles. J Biomed Mater Res A 2014; 102(2): 470-478. 

34. An L, Liu S, Yang Z, Zhang T. Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. Toxicol Lett 2012; 213(2): 220-227. 

35. Eftekhari A, Dizaj SM, Chodari L, Sunar S, Hasanzadeh A, Ahmadian E et al. The promising future of nano-antioxidant therapy against environmental pollutants induced-toxicities. Biomed Pharmacother 2018; 103: 1018-1027. 36. Eftekhari A, Ahmadian E, Azarmi Y, Parvizpur A, Fard JK, Eghbal MA. The effects of cimetidine, N-acetylcysteine, and taurine on thioridazine metabolic activation and induction of oxidative stress in isolated rat hepatocytes. Pharma Chem J 2018; 51(11): 965- 969.

37. Fard J, Hamzeiy H, Sattari M, Eftekhari A, Ahmadian E, Eghbal MA. Triazole rizatriptan induces liver toxicity through lysosomal/mitochondrial dysfunction. Drug Res 2016; 66(09): 470-478. 

38. Wu Y-H, Ursinus J, Zhou J-N, Scheer FA, Ai-Min B, Jockers R, et al. Alterations of melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic nucleus during the depression. J Affect Disord 2013; 148(2-3): 357-367. 

39. Wang JZ, Wang ZF. Role of melatonin in Alzheimer‐like neurodegeneration. Acta Pharmacol Sin 2006; 27(1): 41-49. 40. Tan D-X. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1993; 1: 57-60. 

41. Tan D, Reiter RJ, Manchester LC, Yan M, El-Sawi M, Sainz RM et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2(2): 181-197. 

42. Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan D-X. Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med 2009; 15(1): 43-50. 

43. Mayo JC, Sainz RM, Tan D-X, Hardeland R, Leon J, Rodriguez C et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1- acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol 2005; 165(1-2): 139-149. 

44. Hong Y, Palaksha K, Park K, Park S, Kim HD, Reiter RJ et al. Melatonin plus exercise‐based neurorehabilitative therapy for spinal cord injury. J Pineal Res 2010; 49(3): 201-209. 45. Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, et al. Melatonin stimulates glucose transport via insulin receptor substrate‐1/ phosphatidylinositol 3‐kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res 2006; 41(1): 67-72. 

46. Anhê GF, Caperuto LC, Pereira‐Da‐Silva M, Souza LC, Hirata AE, Velloso LA et al. In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus. J Neurochem 2004; 90(3): 559-566. 

47. Borsello T, Forloni G. JNK signaling: a possible target to prevent neurodegeneration. Curr Pharmaceutic Dec 2007; 13(18): 1875-1886. 48. Goodenough S, Schleusner D, Pietrzik C, Skutella T, Behl C. Glycogen synthase kinase 3β links neuroprotection by 17β-estradiol to key Alzheimer processes. Neurosci 2005; 132(3): 581-589. 

49. Lima ACP, Louzada PR, De Mello FG, Ferreira ST. Neuroprotection against Aβ and glutamate toxicity by melatonin: Are GABA receptors involved? Neurotox Res 2003; 5(5): 323-327. 

50. Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M et al. Inhibition of Alzheimer β-fibrillogenesis by melatonin. J Biol Chem 1998; 273(13): 7185-7188. 

51. Lin L, Huang Q-X, Yang S-S, Chu J, Wang J-Z, Tian Q. Melatonin in Alzheimer’s disease. Int J Mol Sci 2013; 14(7): 14575-14593. 

52. Wang S.S.S, Chen P.H, Hung Y.T. Effects of p-benzoquinone and melatonin on amyloid fibrillogenesis of hen egg-white lysozyme. J Mol Catal B Enzym 2006;43(1-4), 49-57. 

53. Ozansoy M, Ozansoy MB, Yulug B, Cankaya S, Kilic E, Goktekin S et al. Melatonin affects the release of exosomes and tau content in vitro amyloid-beta toxicity model. J Clin Neurosci 2020; 73: 237-244. 

54. Pappolla M, Matsubara E, Vidal R, Pacheco-Quinto J, Poeggeler B, Zagorski M et al. Melatonin treatment enhances Aβ lymphatic clearance in a transgenic mouse model of amyloidosis. Curr Alzheimer Res 2018; 15(7): 637-642. 

55. Yao K, Zhao Y-f, Zu H-b. Melatonin receptor stimulation by agomelatine prevents Aβ-induced tau phosphorylation and oxidative damage in PC12 cells. Drug Des Dev Ther 2019; 13: 387. 

56. Deng Y-q, Xu G-g, Duan P, Zhang Q, Wang J-z. Effects of melatonin on wortmannin-induced tau hyperphosphorylation. Acta Pharmacol Sin 2005; 26(5): 519-526. 

57. Carrascal L, Nunez-Abades P, Ayala A, Cano M. Role of melatonin in the inflammatory process and its therapeutic potential. Curr Pharmaceutic Dec 2018; 24(14): 1563-1588. 

58. Zhu L-Q, Wang S-H, Liu D, Yin Y-Y, Tian Q, Wang X-C et al. Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments. J Neurosci 2007; 27(45): 12211-12220. 

59. Wang X-C, Zhang J, Yu X, Han L, Zhou Z-T, Zhang Y, et al. Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat. Acta Physiol Sin 2005; 57(1): 7-12. 

60. Zhu L, Wang S, Ling Z, Wang Q, Hu M, Wang J. Inhibition of melatonin biosynthesis activates protein kinase a and induces Alzheimer-like tau hyperphosphorylation in rats. Chinese Med Sci J 2005; 20(2): 83-87. 

61. Negi G, Kumar A, Sharma SS. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF‐κB and Nrf2 cascades. J Pineal Res 2011; 50(2): 124-131. 

62. Srinivasan V, Brzezinski A, Pandi-Perumal SR, Spence DW, Cardinali DP, Brown GM. Melatonin agonists in primary insomnia and depression-associated insomnia: are they superior to sedative-hypnotics? Prog Neuropsychopharmacol Biol Psychiatry 2011; 35(4): 913-923. 

63. Filippone A, Lanza M, Campolo M, Casili G, Paterniti I, Cuzzocrea S et al. Protective effect of sodium propionate in Aβ1- 42-induced neurotoxicity and spinal cord trauma. Neuropharmacol 2020; 166: 107977. 

64. Calvo JR, Gonzalez‐Yanes C, Maldonado M. The role of melatonin in the cells of the innate immunity: a review. J Pineal Res 2013; 55(2): 103-120. 

65. Osseni RA, Rat P, Bogdan A, Warnet J-M, Touitou Y. Evidence of prooxidant and antioxidant action of melatonin on human liver cell line HepG2. Life Sci 2000; 68(4): 387-399. 66. Zhai K, Liskova A, Kubatka P, Büsselberg D. Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells. Int J Mol Sci 2020; 21(11): 4177. 

67. Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 2011; 51(1): 1-16. 

68. Martín M, Macías M, Escames G, León J, Acuña-Castroviejo D. Melatonin but not vitamins C and E maintains glutathione homeostasis in t‐butyl hydroperoxide‐induced mitochondrial oxidative stress. FASEB J 2000; 14(12): 1677-1679. 

69. Nguyen XKT, Lee J, Shin EJ, Dang DK, Jeong JH, Nguyen TTL, et al. Liposomal melatonin rescues methamphetamine‐elicited mitochondrial burdens, pro‐apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene. J Pineal Res 2015; 58(1): 86-106. 

70. Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM. Melatonin, cardiolipin, and mitochondrial bioenergetics in health and disease. J Pineal Res 2010; 48(4): 297-310. 

71. Besancon E, Guo S, Lok J, Tymianski M, Lo EH. Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 2008; 29(5): 268-275. 

72. Wang D-d, Jin M-f, Zhao D-j, Ni H. Reduction of mitophagy-related oxidative stress and preservation of mitochondria function using melatonin therapy in an HT22 hippocampal neuronal cell model of glutamate-induced excitotoxicity. Front Endocrinol 2019; 10: 550. 

73. Jürgenson M, Zharkovskaja T, Noortoots A, Morozova M, Beniashvili A, Zapolski M et al. Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid‐predominant mouse model of Alzheimer's disease. J Pharm Pharmacol 2019; 71(11): 1695-1705. 74. Srinivasan V, Cardinali DP, Srinivasan US, Kaur C, Brown GM, Spence DW et al. Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection. Ther Adv Neurol Disord 2011; 4(5): 297-317. 

75. Videnovic A, Noble C, Reid KJ, Peng J, Turek FW, Marconi A, et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson's disease. JAMA Neurol 2014; 71(4): 463-469. 

76. Singhal NK, Srivastava G, Agrawal S, Jain SK, Singh MP. Melatonin as a neuroprotective agent in the rodent models of Parkinson’s disease: is it all set to irrefutable clinical translation? Mol Neurobiol 2012; 45(1): 186-199. 

77. Cardinali DP. Melatonin: clinical perspectives in neurodegeneration. Front Endocrinol 2019; 10: 480. 

78. Maldonado M, Murillo‐Cabezas F, Terron M, Flores L, Tan D, Manchester L et al. The potential of melatonin in reducing morbidity–mortality after craniocerebral trauma. J Pineal Res 2007; 42(1): 1-11. 

79. Asefy Z, Hoseinnejhad S, Ceferov Z. Nanoparticles approaches in neurodegenerative diseases diagnosis and treatment. Neurolog Sci 2021: 1-8. 

80. Juknat AA, Méndez MdVA, Quaglino A, Fameli CI, Mena M, Kotler ML. Melatonin prevents hydrogen peroxide‐induced Bax expression in cultured rat astrocytes. J Pineal Res 2005; 38(2): 84-92. 

81. Wang X. The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther 2009; 15(4): 345-357. 

82. Srivastava AK, Choudhury SR, Karmakar S. Melatonin/polydopamine nanostructures for collective neuroprotection-based Parkinson's disease therapy. Biomater Sci 2020; 8(5): 1345-1363. 

83. An Z, Yan J, Zhang Y, Pei R. Applications of nanomaterials for scavenging reactive oxygen species in the treatment of central nervous system diseases. J Mater Chem B 2020; 8(38): 8748-8767. 

84. Shankar J, Geetha K, Wilson B, Technology. Potential applications of nanomedicine for treating Parkinson's disease. J Drug Deliv Sci Technol 2021: 102793. 

85. Kazemi E, Zargooshi J, Kaboudi M, Heidari P, Kahrizi D, Mahaki B, Mohammadian Y, Khazaei H, Ahmed K. A genome-wide association study to identify candidate genes for erectile dysfunction. Brief Bioinforma 2021;22(4):bbaa338. 

86. Ercisli M., Lechun, G, Azeez S, Hamasalih R, Song S, Aziziaram Z. Relevance of genetic polymorphisms of the human cytochrome P450 3A4 in rivaroxaban-treated patients. Cell Mol Biomed Rep 2021; 1(1): 33-41. 

87. Kotler M, Rodríguez C, Sáinz RM, Antolin I, Menéndez‐Peláez A. Melatonin increases gene expression for antioxidant enzymes in the rat brain cortex. J Pineal Res 1998;24(2):83-9.

Zahra Asefy1 , Ameer Khusro2*, Shakar Mammadova3 , Sirus Hoseinnejhad1 , Aziz Eftekhari1,4*, Saad Alghamdi5 , Anas S. Dablool6 , Mazen Almehmadi7 , Elham Kazemi8 , Muhammad Umar Khayam Sahibzada9*

 1 Department of Pharmacology and Toxicology, Maragheh University of Medical Sciences, Maragheh, Iran 

2 Research Department of Plant Biology and Biotechnology, Loyola College, Chennai, Tamil Nadu, India 

3 Department of Physical Geography, Baku State University, Baku, Azerbaijan 4 Department of Biology and Chemistry, Drohobych Ivan Franko State Pedagogical University, Drohobych, Ukraine 

5 Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, P.O. Box.715, Makkah, 21955, Saudi Arabia 

6 Department of Public Health, Health Sciences College at Al-Leith, Umm Al-Qura University, Makkah, Saudi Arabia 

7 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia 

8 Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran 

9 Department of Pharmacy, Sarhad University of Science & Information Technology, Peshawar 25100, Khyber Pakhtunkhwa, Pakistan