Neuroprotective Role of Polyphenols in Treatment of Neurological Disorders: A Review


avatar Mudasir Maqbool ORCID 1 , * , avatar Mehrukh Zehravi 2

Research Scholar, Department of Pharmaceutical Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
Department of Clinical Pharmacy Girls Section, Prince Sattam Bin Abdul Aziz University Alkharj, Saudia Arabia

how to cite: Maqbool M, Zehravi M. Neuroprotective Role of Polyphenols in Treatment of Neurological Disorders: A Review. Interv Pain Med Neuromod. 2021;1(1):e117170.


The most frequent illnesses characterized by the gradual malfunctioning of brain neurons are neurodegenerative disorders (NDs). Genetic mutations and a range of biological processes can produce NDs. Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS) are all related to oxidative stress (OS). Reduced brain activity has become a greater health threat with a growing elderly population. It causes some pathophysiological alterations and is an important risk factor for a range of neurodegenerative illnesses. An increase in reactive oxygen species (ROS) can cause neuronal cell death, and it is thus essential to control ROS levels to maintain normal neuronal activity. Synthetic medicines are often used to treat neurological disorders; however, harmful effects have been reported. Multiple bodies of research have shown the effectiveness of polyphenols in the treatment of various NDs due to their negligible side effects. This review article describes the neuroprotection effects of polyphenols such as resveratrol, epigallocatechin-3-gallate, curcumin, and quercetin, as well as the signaling pathways and immune response controls through polyphenols.

1. Context

Neurodegenerative disorders (NDs) are a global problem for which no effective therapy or cure is possible. Neurodegenerative disorders are the most common in the elderly. Globally, the number of elderly people with NDs has increased, leading to more deaths. The most common NDs in elders are Parkinson's disease (PD), Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Roughly, 13.26% of the population of China is more than 60, with more than five million people suffering from Alzheimer's disease.

Several reasons complicate the evaluation of neurodegenerative diseases with atrophic changes in brain aging. Many biological factors such as oxidative stress, mitochondrial malfunction, neuronal and glial inflammation, proteins accumulation, and apoptotic pathways activation lead to pathogenesis of these disorders. Because neurodegenerative disorders advance slowly, there is no conclusive treatment option to stop the illness development of these disorders (1-5). Flavonoids were the widely used phytochemicals with distinct therapeutic characteristics in the past few decades. Polyphenols are plant-based phenolic compounds, some of which are accessible in ether or ester forms. Polyphenolic substances contain pharmaceutical flavonoids such as epigallocatechin, catechin, epigallocatechin gallate, and flavonoids such as quercetin and luteolin. Flavonoids are important metabolites found in a wide range of foodstuffs and medicinal plants. Polyphenols have anticancer, antiviral, antioxidant, and antibacterial characteristics. As a result, polyphenolic compounds are acclaimed for some conditions, including neurological issues, as natural remedies.

A variety of sources of polyphenolic compounds have been demonstrated to increase cognitive functioning and minimize brain neuropathy through a variety of mechanisms. The capacity of these components to treat brain diseases is determined not only by their ability to reach the brain and its chemical structure or direct interaction with brain cells or neurons but also by their ability balance the connection between the brain and other neurological axes. According to preclinical research, these bioactive components are protective against illnesses of the brain such as autism, Down's syndrome, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, and psychiatric disorders such as anxiety and sadness (6-13).

2. Polyphenols in Neurological Disorders

2.1. Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurological condition that causes cognitive impairment and loss of memory. Prescribed AD drugs currently provide symptomatic alleviation. If used regularly, there may be substantial responses or bad effects. Natural substances are a preferred alternative to commercial AD medicines. Polyphenols are plant-based secondary antioxidant and neuroprotective metabolites. The development of polyphenols in neurological illness treatment is hindered by their complicated bioactivity and brain absorption. Polyphenol dietary intake has been developed to minimize OS, modify signaling pathways, and decrease the risk of AD through boosting cognitive capacities. Some scientific research has indicated that everyday polyphenols have favorable effects on the pathophysiology of AD. Tau protein-amyloid accumulates in AD, and tau protein-hyperphosphorylation in neurons is induced by intracellular neurofibrillary engravings (NFT). They occur mostly in the hippocampus and brain cortex, which cause neuronal degeneration (14-19). The formation of amyloid aggregated protein in the brains of AD patients causes inflammation and oxidative damage. Two further reasons for this syndrome include cholinergic neurotransmission depletion and excessive glutamatergic neurotransmission.

Curcumin is a key polyphenol present in turmeric. Turmeric powder comprises the turmeric plant's yellow-orange part. Due to its various bioactivities and absence of unwanted effects, curcumin has gained more attention during the last few decades. In ancient times, it was used in India to cure some diseases. Curcumin is a strong antioxidant, anti-cancer, and anti-inflammatory agent. Curcumin can be consistent with amyloid-beta (Aβ) by overcoming the kappa B nuclear factor (NF-κβ), which allows this polyphenol to halt the degenerative AD process. Curcumin is also a lipophilic substance that can easily overpass the blood-brain barrier and join plaques to limit the aggregation and dispersion of amyloid peptides. Increasing data suggest the way that PI3K/Akt/GSK-3β flags are directly influenced by Aβ and AD-brain alterations. Neurotrophins engage in the PI3K/Akt signaling pathway to ensure neuronal continuity and plasticity. Their act may be activated by neurotrophic factors coming from the brain (BDNF). According to Kim et al. (2005) review, curcumin is the most powerful antioxidant, with around 214 antioxidant compounds. Curcumin improved cognitive impairments in elderly rats (20-28).

Resveratrol is the most important non-flavonoid present in red wine, almonds, and grapes. A wide spectrum of pharmacological activity has been examined, including anti-inflammatory, antioxidant, anti-carcinogenic, and anti-mutagenic properties. Most models of AD are in vitro and in vivo. Resveratrol has proven to be neuroprotective. Besides its antioxidant and anti-inflammatory characteristics, research shows that resveratrol helps divide the non-amyloidogenic amyloid precursor protein (APP). It also helps eliminate neurotoxic amyloid-beta (Aβ) peptides that play a crucial role in the prevention and development of AD pathophysiology. Resveratrol also lowers neuronal cell loss through some additional mechanisms, the main one being NAD+-dependent histone-deacetylase enzymes known as sirtuins. Resveratrol can be used as a non-oxidant agent due to decreasing ROS formation, raising the magnitude of GSH and intracellular Ca21 in neurons, and changing the way of second messengers, calcium-dependent AMP-activated protein (cAMP), and nitric oxide (29-33). Resveratrol attaches to the plaques of Aβ and leads to the removal of the Aβ peptide, and also prevents AChE activity in in vitro cells.

Green tea includes several epigallocatechin 3-gallates, a reasonably common flavonoid of catechin. Besides, EGCG has antioxidant and some pharmacological properties and was examined in neurological diseases, atherosclerosis, and cancer. This component has gained a great deal of interest for its potential to prevent neurodegeneration in recent decades. It is noteworthy to see that NDs are negatively related to tea drinking. The administration of D-gal in AD models has a crucial role in reducing Aβ according to studies of AD models supplied with EGCG. A study indicated that EGCG administration helped avoid brain neuron death by reducing the activity of NF-κβ and Extracellular Receptor Kinase (ERK) and decreasing the concentrations of β- and γ-secretases (i.e., APP cleaving enzymes) (34-39).

2.2. Parkinson’s Disease

Parkinson's disease is the most frequent human neurodegenerative disorder after AD. The dopaminergic neurons in the substantial pars compacta (SNpc) degrade because of a breakdown in motor and cognitive abilities, leading to PD. The aggregation in the cytoplasm of a selected neuron of protein inclusions containing alpha-synuclein and ubiquitin leads to the creation of marked lesions known as Lewy structures, which causes neuronal death. Medications used to treat AD and PD nowadays do not stop neurodegenerative processes but just reduce the symptoms. A neurodegenerative disease characterized by neurocyte loss in hippocampal tissues and cognitive impairment is a clinically complex neurodegenerative disease. Hippocampal brain loss inhibition is a promising strategy for PD treatment. When compared to Caucasians, the use of turmeric/curcumin is hypothesized as an explanation for India's low prevalence of AD and PD (40-45). The findings show that Indian brains have about 40% fewer melanized nigral neurons than Caucasian brains. The decreasing prevalence of PD in India is therefore associated with dietary choices. Turmeric intake protects against diseases such as diabetes and cancer. Recent research has shown that curcumin has a neuroprotective impact in lowering the cytotoxicity caused by cadmium. Curcumin has proven to be an efficient treatment for PD induced by homocysteine in rats. Curcumin was reported to assist neuronal regeneration in a PD model by activating the signaling pathways of Trk/PI3K, which elevates the BDNF level. The main biological function of curcumin is its antioxidant impact. The antioxidant impact of curcumin raises the levels of striatal dopamine, protects neurons, and chelates SN and Fe2+ in the 6-hydroxy dopamine (6-OHDA) PD rat model. Phenolic rings and diketone groups of curcumin limit the formation of OH-, H2O2-, and superoxides (46-50). Curcumin has been effectively investigated in various models of PD. Curcumin therapy promotes mitochondrial protection with direct impacts on therapy in a range of PD models. Curcumin therapy enhances Cu/Zn SOD, rescues mitochondrial membrane potential, and restores cell survival in MES 23.5-treated cells with 6-hydroxy dopamine (6-OHDA). The density of dopaminergic neurons may be increased by curcumin therapy in SN. According to prior research, curcumin's neuroprotective activity was linked to neurogenesis. Resveratrol was found to have protective effects in a PD rat model generated by 6-OHDA. Chronic inflammation, oxidative stress, mitochondrial malfunction, and dopaminergic loss of the neuron are all expected to occur in the substantial nigra. Resveratrol promotes a reduction in cyclooxygenase (COX-2) and tumor necrosis factor mRNA concentrations. The expression of the COX-2 protein in substantial nigra is also diminished. Resveratrol can inhibit the expression of pro-inflammatory enzymes (COX-2) and cytokines (TNF-α) that interfere with the synthesis of prostaglandins (e.g. COX-2) (51-55). Substantial nigra injection of 6-OHDA induces the death of dopamine neurons that may imitate the early stages of PD. Besides, COX-2 and TNF-α mRNA over-expression is a cause of PD. Following resveratrol administration, the levels of COX-2, TNF-α mRNA, and protein lowered in a rat model of PD. Therefore, it is notable that resveratrol has positive effects on PD generated by 6-OHDA in rats. These effects can be produced by a reduction in the expression of COX-2, TNF-α mRNA, and protein. More research is needed to employ resveratrol for the treatment of PD. The stimulation of microglia is decreased when quercetin is administered by 1-methyl-4-phenylpyridinium (MMP; a forerunner to PD pathogenesis). In PD, the model cell quercetin destroys the cell, but such metabolites do not influence cell survival due to their restricted absorption (54, 56-60).

2.3. Ischemic Stroke

Stroke is the world's third-biggest cause of mortality. By changing our diet to contain more polyphenols, we can lessen the likelihood and severity of stroke. Several models were employed to detect whether various polyphenols have excellent advantages. Green tea is a major polyphenol source. Hypoxia generates ischemic damage, which promotes inflammation and neuronal damage. Green tea polyphenol, EGCG, has shown neuroprotective effects in the brain ischemia mouse model via reducing metalloproteinase (MMP) matrices. Green tea polyphenols are found to protect neurons against the damage caused by hypoxia, modulating the inflammatory cascade and limiting the potential for trans-membrane degeneration. Quercetin plays a vital role in avoiding ischemic injury by lowering lipid peroxidation and ion channel acid sensing, both contributing to the dysregulation of the ion channel. With the same antioxidant analyses as green tea polyphenols, quercetin condenses the amount of MMP-9 in tests for cerebral ischemia (CI) and lowered blood-brain interference (61-65). Rutin inhibits p53, a protein that promotes stroke necrosis and thus limits neuronal damage in cerebral ischemia. Glutathione peroxidase and glutathione reductase reduce inflammatory cytokines in ischemic stroke model rats. Baicalin, a type of flavonoid, has been demonstrated to diminish ischemic stroke damage, p38 mitogen-activated protein kinase (MAPK), oxidative stress, caspase-3, and the toll-like receptor (TLR2/4) pathway by inhibiting these pathways (66-69).

2.4. Multiple Sclerosis

Multiple Sclerosis (MS) is a highly threatening and disabling disease that destroys the nerve sheath of myelin, causing lifelong nerve damage. It has an effect on how the body functions, especially the limbs and extremities. Multiple sclerosis is the most common non-traumatic disabling disorder that affects young individuals. Multiple sclerosis is becoming more widespread over the world, as is its economic impact. Despite that complex gene-environment interactions are likely to play a significant role, the underlying etiology of MS and the mechanisms driving an increase in patients are unknown. According to MS epidemiology, low blood vitamin D levels, smoking, childhood obesity, and infection with the Epstein–Barr virus all have a part in the disease's progression. Thanks to breakthroughs in diagnostic techniques and criteria, people with MS can now be detected earlier in their illness courses. In addition, the number, efficacy, and risk of MS treatments have all increased dramatically. A diagnosis of 'pre-symptomatic MS' is now possible, which could lead to the exploration of new preventive medicines (70, 71).

3. Multiple Sclerosis Therapies

Symptoms can be decreased, and the immune system can be improved with a doctor and a complete and effective treatment. Polyphenols are one of the therapeutically helpful chemicals for MS treatment. Resveratrol, quercetin, epigallocatechin-3-gallate, and myricetin are some of the polyphenols utilized for MS treatment due to their advantages and efficacy. Polyphenols are examined according to many models for MS treatment by reducing inflammation and breaking the immune system. Polyphenols demonstrated to be able to reduce inflammation by modifying the cytokine pathways in various studies (for example, IL-β and TNF-α). In this method, brain demyelination is reduced, and normal limb function is restored. Polyphenols can be utilized in age-related MS and amyotrophic lateral sclerosis as prophylactics, keeping their effectiveness in mind (72-74).

4. Conclusion

Polyphenols are highly effective in both therapeutic and pharmacological settings. They can be found in a wide range of fruits and dietary meals. Various polyphenols have been studied for their impact on neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Neurodegenerative diseases are driven by inflammation, oxidative stress, and abnormal mitochondrial function, according to new research. For the treatment and prevention of many disorders, new therapeutic approaches that target specific genes and proteins are required. Inflammation, ion channels, reactive oxygen species (ROS), and neurotransmitters are all controlled and regulated by polyphenols. Antioxidant capabilities are found in polyphenols. Neuroprotective effects are found in polyphenols, including EGCG, resveratrol, and quercetin. Polyphenols have been shown to activate antioxidant pathways such as Nrf2 in numerous studies. Polyphenols can also block the NFB and STAT signaling pathways. Polyphenols control the immune response by inhibiting proinflammatory cytokines, including TNF-α and IFN-γ. Polyphenols do, in fact, provide neuronal damage prevention.


  • 1.

    Duraes F, Pinto M, Sousa E. Old drugs as new treatments for neurodegenerative diseases. Pharmaceuticals (Basel). 2018;11(2). [PubMed ID: 29751602]. [PubMed Central ID: PMC6027455].

  • 2.

    Uddin MS, Al Mamun A, Kabir MT, Ahmad J, Jeandet P, Sarwar MS, et al. Neuroprotective role of polyphenols against oxidative stress-mediated neurodegeneration. Eur J Pharmacol. 2020;886:173412. [PubMed ID: 32771668].

  • 3.

    Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules. 2019;24(8). [PubMed ID: 31013638]. [PubMed Central ID: PMC6514564].

  • 4.

    Li GH, Li P, Lu L, Li Z, Mo MS, Chen X, et al. The outcome and burden of Chinese patients with neurodegenerative diseases: A 10-year clinical feature study. Int J Clin Pract. 2020;74(9). e13534. [PubMed ID: 32418282].

  • 5.

    Maher P. The potential of flavonoids for the treatment of neurodegenerative diseases. Int J Mol Sci. 2019;20(12). [PubMed ID: 31234550]. [PubMed Central ID: PMC6627573].

  • 6.

    Burton DA, Nicholson G, Hall GM. Anaesthesia in elderly patients with neurodegenerative disorders: Special considerations. Drugs Aging. 2004;21(4):229-42. [PubMed ID: 15012169].

  • 7.

    Rengasamy KRR, Khan H, Gowrishankar S, Lagoa RJL, Mahomoodally FM, Khan Z, et al. The role of flavonoids in autoimmune diseases: Therapeutic updates. Pharmacol Ther. 2019;194:107-31. [PubMed ID: 30268770].

  • 8.

    Jiang Z, Zhang J, Cai Y, Huang J, You L. Catechin attenuates traumatic brain injury-induced blood-brain barrier damage and improves longer-term neurological outcomes in rats. Exp Physiol. 2017;102(10):1269-77. [PubMed ID: 28678393].

  • 9.

    Li S, Li SK, Gan RY, Song FL, Kuang L, Li HB. Antioxidant capacities and total phenolic contents of infusions from 223 medicinal plants. Ind Crops Prod. 2013;51:289-98.

  • 10.

    Wang TY, Li Q, Bi KS. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian J Pharm Sci. 2018;13(1):12-23. [PubMed ID: 32104374]. [PubMed Central ID: PMC7032191].

  • 11.

    Choi DY, Lee YJ, Hong JT, Lee HJ. Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer's disease. Brain Res Bull. 2012;87(2-3):144-53. [PubMed ID: 22155297].

  • 12.

    Vauzour D. Dietary polyphenols as modulators of brain functions: Biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev. 2012;2012:914273. [PubMed ID: 22701758].

  • 13.

    Westfall S, Pasinetti GM. The gut microbiota links dietary polyphenols with management of psychiatric mood disorders. Front Neurosci. 2019;13:1196. [PubMed ID: 31749681]. [PubMed Central ID: PMC6848798].

  • 14.

    Veurink G, Perry G, Singh SK. Role of antioxidants and a nutrient rich diet in Alzheimer's disease. Open Biol. 2020;10(6):200084. [PubMed ID: 32543351]. [PubMed Central ID: PMC7333894].

  • 15.

    Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev. 2009;2(5):270-8. [PubMed ID: 20716914].

  • 16.

    Brglez Mojzer E, Knez Hrncic M, Skerget M, Knez Z, Bren U. Polyphenols: Extraction methods, antioxidative action, bioavailability and anticarcinogenic effects. Molecules. 2016;21(7). [PubMed ID: 27409600]. [PubMed Central ID: PMC6273793].

  • 17.

    Jiang T, Sun Q, Chen S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease. Prog Neurobiol. 2016;147:1-19. [PubMed ID: 27769868].

  • 18.

    Hamaguchi T, Ono K, Murase A, Yamada M. Phenolic compounds prevent Alzheimer's pathology through different effects on the amyloid-beta aggregation pathway. Am J Pathol. 2009;175(6):2557-65. [PubMed ID: 19893028].

  • 19.

    Butterfield DA, Reed T, Newman SF, Sultana R. Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Biol Med. 2007;43(5):658-77. [PubMed ID: 17664130]. [PubMed Central ID: PMC2031860].

  • 20.

    Mariani E, Polidori MC, Cherubini A, Mecocci P. Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;827(1):65-75. [PubMed ID: 16183338].

  • 21.

    Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets. 2011;12(3):332-47. [PubMed ID: 20955148].

  • 22.

    Farooqui T, Farooqui AA. Curcumin: Historical background, chemistry, pharmacological action, and potential therapeutic value. Curcumin for neurological and psychiatric disorders: Neurochemical and pharmacological properties. Massachusetts, USA: Academic Press; 2019. p. 23-44.

  • 23.

    Sharma RA, Gescher AJ, Steward WP. Curcumin: The story so far. Eur J Cancer. 2005;41(13):1955-68. [PubMed ID: 16081279].

  • 24.

    Nam SM, Choi JH, Yoo DY, Kim W, Jung HY, Kim JW, et al. Effects of curcumin (Curcuma longa) on learning and spatial memory as well as cell proliferation and neuroblast differentiation in adult and aged mice by upregulating brain-derived neurotrophic factor and CREB signaling. J Med Food. 2014;17(6):641-9. [PubMed ID: 24712702].

  • 25.

    Kapitulnik J. Drug transport and metabolism in the blood-brain barrier. Front Pharmacol. 2011;2:37. [PubMed ID: 21811462].

  • 26.

    Hoppe JB, Coradini K, Frozza RL, Oliveira CM, Meneghetti AB, Bernardi A, et al. Free and nanoencapsulated curcumin suppress beta-amyloid-induced cognitive impairments in rats: Involvement of BDNF and Akt/GSK-3beta signaling pathway. Neurobiol Learn Mem. 2013;106:134-44. [PubMed ID: 23954730].

  • 27.

    Zhong Y, Zhu Y, He T, Li W, Li Q, Miao Y. Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway. Int J Mol Med. 2019;43(1):294-304. [PubMed ID: 30365051]. [PubMed Central ID: PMC6257855].

  • 28.

    Kim H, Park BS, Lee KG, Choi CY, Jang SS, Kim YH, et al. Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J Agric Food Chem. 2005;53(22):8537-41. [PubMed ID: 16248550].

  • 29.

    Liang Z, Owens CL, Zhong GY, Cheng L. Polyphenolic profiles detected in the ripe berries of Vitis vinifera germplasm. Food Chem. 2011;129(3):940-50. [PubMed ID: 25212322].

  • 30.

    de la Lastra CA, Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. Mol Nutr Food Res. 2005;49(5):405-30. [PubMed ID: 15832402].

  • 31.

    Braidy N, Jugder BE, Poljak A, Jayasena T, Mansour H, Nabavi SM, et al. Resveratrol as a potential therapeutic candidate for the treatment and management of Alzheimer's disease. Curr Top Med Chem. 2016;16(17):1951-60. [PubMed ID: 26845555].

  • 32.

    Schemies J, Uciechowska U, Sippl W, Jung M. NAD(+) -dependent histone deacetylases (sirtuins) as novel therapeutic targets. Med Res Rev. 2010;30(6):861-89. [PubMed ID: 19824050].

  • 33.

    Li F, Gong Q, Dong H, Shi J. Resveratrol, a neuroprotective supplement for Alzheimer's disease. Curr Pharm Des. 2012;18(1):27-33. [PubMed ID: 22211686].

  • 34.

    Lee EO, Park HJ, Kang JL, Kim HS, Chong YH. Resveratrol reduces glutamate-mediated monocyte chemotactic protein-1 expression via inhibition of extracellular signal-regulated kinase 1/2 pathway in rat hippocampal slice cultures. J Neurochem. 2010;112(6):1477-87. [PubMed ID: 20050970].

  • 35.

    Elbling L, Weiss RM, Teufelhofer O, Uhl M, Knasmueller S, Schulte-Hermann R, et al. Green tea extract and (-)-epigallocatechin-3-gallate, the major tea catechin, exert oxidant but lack antioxidant activities. FASEB J. 2005;19(7):807-9. [PubMed ID: 15738004].

  • 36.

    Weinreb O, Amit T, Mandel S, Youdim MB. Neuroprotective molecular mechanisms of (-)-epigallocatechin-3-gallate: A reflective outcome of its antioxidant, iron chelating and neuritogenic properties. Genes Nutr. 2009;4(4):283-96. [PubMed ID: 19756809].

  • 37.

    Pervin M, Unno K, Ohishi T, Tanabe H, Miyoshi N, Nakamura Y. Beneficial effects of green tea catechins on neurodegenerative diseases. Molecules. 2018;23(6). [PubMed ID: 29843466]. [PubMed Central ID: PMC6099654].

  • 38.

    Chan S, Kantham S, Rao VM, Palanivelu MK, Pham HL, Shaw PN, et al. Metal chelation, radical scavenging and inhibition of Abeta(4)(2) fibrillation by food constituents in relation to Alzheimer's disease. Food Chem. 2016;199:185-94. [PubMed ID: 26775960].

  • 39.

    Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, et al. Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behav Brain Res. 2014;271:116-21. [PubMed ID: 24914461].

  • 40.

    Kujawska M, Jodynis-Liebert J. Polyphenols in Parkinson's disease: A systematic review of in vivo studies. Nutrients. 2018;10(5). [PubMed ID: 29783725]. [PubMed Central ID: PMC5986521].

  • 41.

    Kurosinski P, Guggisberg M, Gotz J. Alzheimer's and Parkinson's disease--overlapping or synergistic pathologies? Trends Mol Med. 2002;8(1):3-5. [PubMed ID: 11796255].

  • 42.

    Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112. [PubMed ID: 24795567].

  • 43.

    Choi AY, Choi JH, Lee JY, Yoon KS, Choe W, Ha J, et al. Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. Neurochem Int. 2010;57(2):143-52. [PubMed ID: 20493918].

  • 44.

    Oguzturk H, Ciftci O, Aydin M, Timurkaan N, Beytur A, Yilmaz F. Ameliorative effects of curcumin against acute cadmium toxicity on male reproductive system in rats. Andrologia. 2012;44(4):243-9. [PubMed ID: 22257170].

  • 45.

    Ganguli M, Chandra V, Kamboh MI, Johnston JM, Dodge HH, Thelma BK, et al. Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study. Arch Neurol. 2000;57(6):824-30. [PubMed ID: 10867779].

  • 46.

    Muthane U, Yasha TC, Shankar SK. Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India. Ann Neurol. 1998;43(3):283-7. [PubMed ID: 9506543].

  • 47.

    Sinha R, Anderson DE, McDonald SS, Greenwald P. Cancer risk and diet in India. J Postgrad Med. 2003;49(3):222-8. [PubMed ID: 14597785].

  • 48.

    Mansouri Z, Sabetkasaei M, Moradi F, Masoudnia F, Ataie A. Curcumin has neuroprotection effect on homocysteine rat model of Parkinson. J Mol Neurosci. 2012;47(2):234-42. [PubMed ID: 22418789].

  • 49.

    Yang J, Song S, Li J, Liang T. Neuroprotective effect of curcumin on hippocampal injury in 6-OHDA-induced Parkinson's disease rat. Pathol Res Pract. 2014;210(6):357-62. [PubMed ID: 24642369].

  • 50.

    Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease. Free Radic Res. 2005;39(10):1119-25. [PubMed ID: 16298737].

  • 51.

    Wang J, Du XX, Jiang H, Xie JX. Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-oxidation and nuclear factor-kappa B modulation in MES23.5 cells. Biochem Pharmacol. 2009;78(2):178-83. [PubMed ID: 19464433].

  • 52.

    Vajragupta O, Boonchoong P, Watanabe H, Tohda M, Kummasud N, Sumanont Y. Manganese complexes of curcumin and its derivatives: Evaluation for the radical scavenging ability and neuroprotective activity. Free Radic Biol Med. 2003;35(12):1632-44. [PubMed ID: 14680686].

  • 53.

    Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, et al. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem. 2008;283(21):14497-505. [PubMed ID: 18362141].

  • 54.

    Jin F, Wu Q, Lu YF, Gong QH, Shi JS. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats. Eur J Pharmacol. 2008;600(1-3):78-82. [PubMed ID: 18940189].

  • 55.

    Martin AR, Villegas I, Sanchez-Hidalgo M, de la Lastra CA. The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model. Br J Pharmacol. 2006;147(8):873-85. [PubMed ID: 16474422]. [PubMed Central ID: PMC1760707].

  • 56.

    Lee CS, Sauer H, Bjorklund A. Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat. Neuroscience. 1996;72(3):641-53. [PubMed ID: 9157311].

  • 57.

    Bournival J, Plouffe M, Renaud J, Provencher C, Martinoli MG. Quercetin and sesamin protect dopaminergic cells from MPP+-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system. Oxid Med Cell Longev. 2012;2012:921941. [PubMed ID: 22919443].

  • 58.

    Mir SA, Gani I, Dar MA, Maqbool M. Animal models in diabetes mellitus: An overview. J Drug Deliv Ther. 2019;9(1):472-5.

  • 59.

    Lv C, Hong T, Yang Z, Zhang Y, Wang L, Dong M, et al. Effect of quercetin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson's disease. Evid Based Complement Alternat Med. 2012;2012:928643. [PubMed ID: 22454690].

  • 60.

    Mukai R, Kawabata K, Otsuka S, Ishisaka A, Kawai Y, Ji ZS, et al. Effect of quercetin and its glucuronide metabolite upon 6-hydroxydopamine-induced oxidative damage in Neuro-2a cells. Free Radic Res. 2012;46(8):1019-28. [PubMed ID: 22404304].

  • 61.

    Ashafaq M, Raza SS, Khan MM, Ahmad A, Javed H, Ahmad ME, et al. Catechin hydrate ameliorates redox imbalance and limits inflammatory response in focal cerebral ischemia. Neurochem Res. 2012;37(8):1747-60. [PubMed ID: 22570178].

  • 62.

    Park JW, Hong JS, Lee KS, Kim HY, Lee JJ, Lee SR. Green tea polyphenol (-)-epigallocatechin gallate reduces matrix metalloproteinase-9 activity following transient focal cerebral ischemia. J Nutr Biochem. 2010;21(11):1038-44. [PubMed ID: 19962294].

  • 63.

    Panickar KS, Polansky MM, Anderson RA. Green tea polyphenols attenuate glial swelling and mitochondrial dysfunction following oxygen-glucose deprivation in cultures. Nutr Neurosci. 2009;12(3):105-13. [PubMed ID: 19356313].

  • 64.

    Yao Y, Han DD, Zhang T, Yang Z. Quercetin improves cognitive deficits in rats with chronic cerebral ischemia and inhibits voltage-dependent sodium channels in hippocampal CA1 pyramidal neurons. Phytother Res. 2010;24(1):136-40. [PubMed ID: 19688719].

  • 65.

    Lee JK, Kwak HJ, Piao MS, Jang JW, Kim SH, Kim HS. Quercetin reduces the elevated matrix metalloproteinases-9 level and improves functional outcome after cerebral focal ischemia in rats. Acta Neurochir (Wien). 2011;153(6):1321-9. discussion 1329. [PubMed ID: 21120545].

  • 66.

    Khan MM, Ahmad A, Ishrat T, Khuwaja G, Srivastawa P, Khan MB, et al. Rutin protects the neural damage induced by transient focal ischemia in rats. Brain Res. 2009;1292:123-35. [PubMed ID: 19631195].

  • 67.

    Abd-El-Fattah AA, El-Sawalhi MM, Rashed ER, El-Ghazaly MA. Possible role of vitamin E, coenzyme Q10 and rutin in protection against cerebral ischemia/reperfusion injury in irradiated rats. Int J Radiat Biol. 2010;86(12):1070-8. [PubMed ID: 20712430].

  • 68.

    Tu XK, Yang WZ, Liang RS, Shi SS, Chen JP, Chen CM, et al. Effect of baicalin on matrix metalloproteinase-9 expression and blood-brain barrier permeability following focal cerebral ischemia in rats. Neurochem Res. 2011;36(11):2022-8. [PubMed ID: 21678122].

  • 69.

    Tu XK, Yang WZ, Shi SS, Chen Y, Wang CH, Chen CM, et al. Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia. Inflammation. 2011;34(5):463-70. [PubMed ID: 20859668].

  • 70.

    Dobson R, Giovannoni G. Multiple sclerosis - a review. Eur J Neurol. 2019;26(1):27-40. [PubMed ID: 30300457].

  • 71.

    Carroll D. An examination of the relationship between the prevalence of multiple sclerosis and the geological environment specifically exposure to indoor radon before the age of 15 years [master's thesis]. Sligo, Ireland: Institute of Technology Sligo; 2005.

  • 72.

    Herges K, Millward JM, Hentschel N, Infante-Duarte C, Aktas O, Zipp F. Neuroprotective effect of combination therapy of glatiramer acetate and epigallocatechin-3-gallate in neuroinflammation. PLoS One. 2011;6(10). e25456. [PubMed ID: 22022398].

  • 73.

    Yahfoufi N, Alsadi N, Jambi M, Matar C. The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients. 2018;10(11). [PubMed ID: 30400131]. [PubMed Central ID: PMC6266803].

  • 74.

    Hendriks JJ, de Vries HE, van der Pol SM, van den Berg TK, van Tol EA, Dijkstra CD. Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study. Biochem Pharmacol. 2003;65(5):877-85. [PubMed ID: 12628496].