INTRODUCTION:

Quercetin (Que; 3, 3′,4′,5,7-pentahydroxyflavone) is a flavonoid compound with several crucial activities for human health^[1-3]. The studies on flavonoids has been going on with developing interest as they act through physiological mechanisms and several signaling pathways involved in many medical diseases^[4-15]. Flavonoids are also the main polyphenolic ingredients that show a wide range of biological effects, including anti-inflammatory, antioxidant, antithrombotic, antiallergic, analgesic, antibacterial, and vasodilatory effects^[15-30]. Several studies have indicated that quercetin was effective for human due to its antioxidant, anti-inflammatory, antiviral, antimicrobial, antiulcerogenic, antineoplastic, cytotoxic, mutagenic, antihepatotoxic, hypolipidemic, antihypertensive, and antiplatelet effects^[31-41].

studies have indicated the protective effect of quercetin against neurodegenerative diseases^[42]. Also, various studies have reported the protective eﬀects of flavonoids such as quercetin against natural and chemical toxic agents in nervous system^[42]. Thus, the present study was designed to review the studies on the protective effects of quercetin against neurodegenerative diseases induced by natural and chemical agents.

METHODS:

The scientific databases such as MEDLINE, PubMed, Scopus, Web of Science and Google Scholar from 1990 to present was searched to identify online scientific literatures about antidotal and protective effects of quercetin against neurotoxic agents. The keywords for the search were: quercetin, toxic agents, and neurodegenerative disease.

RESULTS:

Lead:

Lead (Pb) is one of the major toxic heavy metals, causing severe tissue injury in both human and animal ^[43]. Oxidative stress has been found as an important mechanism involved in lead-induced neurodegenerative diseases such as memory impairment^[44]. Nitric oxide (NO) has a main role in the brain function such as cerebral blood flow, synaptogenesis, neurotransmission, neuroendocrine release. NO is generated by the conversion of L-arginine to L-citrulline by nitric oxide synthases (NOS)^[44]. Lead can disturb events involved in nitric oxide synthase (NOS), with crucial effects on learning and memory^[45]. Lead also affects NOS expression. Lead changes Ca2+-dependent transcription elements for nNOS (the cyclic-AMP-response element-binding protein, CREB; cyclic adenosine monophosphate (cAMP) and eNOS (activator protein 1, AP-1) to reduce protein expression^[46]. Lead decreases CREB phosphorylation by modifying protein kinase B (Akt), extra-cellular signal-regulated kinase (ERK), protein kinase A (PKA) and calcium/calmodulin kinase II (CaMKII). These kinases are involved in the learning and memory signaling pathways. Quercetin (15 and 30 mg/kg, for 3 months, PO) ameliorated neurotoxicity via increasing NO production in the brains of lead-exposed mice. In addition, it was reported that quercetin elevated the phosphorylations of Akt, CaMKII nNOS, eNOS, and CREB in brains of lead-treated animals^[46]. The study suggested that quercetin can ameliorate lead-induced neurotoxicity via improving PKA, Akt, NOS, CaMKII, and CREB activities^[46].

Cadmium:

Cadmium (Cd) is another toxic heavy metals that affects nervous system^[47,48]. Cd causes increase in blood–brain barrier (BBB) permeability, enters into the cells through calcium channels and accumulates in the brain^[48]. Cd leads to neuronal dysfunction as well as changes cholinergic and purinergic neurotransmission systems, antioxidant levels and inflammatory responses^[49]. Acetylcholine (ACh) is an important neurotransmitter of cholinergic system that plays critical functions including memory, learning, movement control, and regulation of cerebral blood ﬂow^[49]. The levels of ACh are modulated by acetylcholine esterase (AChE), which is a membrane-bound enzyme in the brain. AChE may lead to several damages in brain when exposed to the Cd^[50]. AChE activity in brain is increased following exposure to Cd that its increase causes rapid ACh degradation and reduction of stimulation of ACh receptors^[51]. Similarly to the modifications in the cholinergic function, Cd changes in the activity of purinergic neurotransmission system^[52]. Cd increases the activities of NTPDase, 50-nucleotidase, and ADA in synaptosomes from cerebral cortex and subsequently converts adenosine into inosine, decreases the levels of adenosine in brain synapses. Over-production of ROS is one of the main mechanisms involved in neurotoxicity induced by Cd. Thus, antioxidant agents such as quercetin may be effective against cd-induced neurotoxicity^[52].The study conducted by Abdalla et al., 2013 indicated that quercetin (5, 25 or 50 mg/Kg, PO, for 45 days) ameliorated AChE, NTPDase, 5-nucleotidase, and ADA activities increase in the rats exposed to Cd. The study suggested that quercetin improved neurological disorders associated with Cd exposure by modulating cholinergic and purinergic system^[52]. They also indicated that quercetin (5, 24 and 50 mg/kg, PO, 45 days) was effective against Cd-induced memory impairment and anxiogenic-like behavior via inhibiting changes in oxidative stress indices, AChE and Na(+),K(+)-ATPase activities^[53]. Quercetin (15mg/kg, IP, starting 2 days before to Cd injection, 32 days) protected against the Cd-caused neuronal injury in frontal cortex of rats. The study sugsted that quercetin was effective against Cd-induced neurotoxicity via decreasing MDA and caspase 3 levels and increasing the activitis of enzymatic antioxidants (SOD, GPPx and CAT) in the frontal cortex tissue^[54]. In addition, querceitn inhibited Cd-induced toxicity in hippocampus of rats via decreasing MDA and protein carbonyl levels and increasing SOD and CAT activities ^[55]. Quercetin (50 and 100 mg/kg) inhibited memory impairment in adulthood mice that was born by female mice exposed to Cd during lactation by modulating oxidative stress^[56]. Quercetin (25 mg//kg, PO, 28 days) also improved cadmium-induced cognitive deficits related to brain cholinergic dysfunctions in rats. Quercetin inhibited Cd-induced cahnges in mRNA expression of cholinergic-muscarinic receptors (M1, M2, and M4), acetyltransferase (ChAT) and AChE. The protective effect of quercetin on cholinergic system was related to its antioxidant activity, which decreased ROS generation and increased mitochondrial integrity by requlating apoptosis and MAP kinase signaling pathways^[57]. Quercetin (25mg/kg, PO, 28 days) was able to ameliorate cadmium-induced motor dysfunctions by modulating dopaminergic signaling in rat brain^[58].

Arsenic:

Arsenic is a toxic heavy metals that disturbs the functional of several tissues including brain. Quercetin and nanocapsulated quercetin (500µM) combats against arsenic-caused oxidative damage in brain cells of rat model by increasing antioxidant levels^[59].

Chromium:

Chromium is a heavy metals that is used by human for industrial production. In addition, this metal is found in air as Cr (III) and Cr (VI) that Cr (VI) is being highly toxic by convertion to Cr (III) that passes in to cell membrane and attaches to macromolecules. Injection of Cr to the females during lactation induced memory impairment and oxidative stress in first generation mice in their adulthood. Quercetin (25, 50 and 100 mg/kg) modulated these neurotoxic effects of Cr via increasing the activities of GST and CAT as well as decreasing MDA levels in the brain tissue^[60].

Copper:

Copper is an “essential mineral” that is very toxic at high levels. Copper causes oxidative stress by induction of Fenton-type redox reactions. However, copper toxicity is usually occurred following the disruption of the modulation of absorption, distribution, and excretion of this metal. It was suggested that copper toxicity may be associated with neurodegenerative diseases such as Alzheimer's disease. Quercetin nanoparticles (0.25, 0.5 and 0.75 g) ameliorated neurodegenerative Alzheimer's disease induced by Cu(II) via modulating oxidative stress^[61].

Lipopolysaccharide:

Lipopolysaccharide (LPS) causes neurodegenerative diseases by induction of inflammatory mediators in the brain of experimental models^[62]. It is suggested that inhibition of microglia-mediated neuroinflammation is an effective strategy for treatment of neurodegenerative diseases. In this regards, Kao et al., 2010 indicated that quercetin (10µM) decreased the NO production as wells as iNOS expression in microglia cells. Also, it down-regulated the expression of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, Akt, Src, Janus kinase-1, Tyk2, signal transducer and activator of transcription-1, and NF-kB. Quercetin combated against free radicals and inhibited the serine/threonine and tyrosine phosphatase activities. Additionally, it disturbed the accumulation of lipid rafts, the main step for inflammatory signaling. The findings suggested that the anti-inflammatory effects of quercetin may be related to its anti-oxidant and raft disrupting effects. In addition, its down-regulating effects on iNOS expression and NO production decreased inflammation^[63]. The study conducted by Sun et al., 2015 indicated that the inhibitory effects of quercetin on inflammatory responses may be related to its down-regulatory effects on the NF-κB pathway and its up-regulatory effects on the Nrf2 pathway in murine BV-2 microglial cells. The results also indicated that the inhibitory effects of quercetin on LPS-induced NO production and also stimulation of Nrf2-induced heme-oxygenase-1 (HO-1) protein expression was 10 folds more potent than cyanidin (one of the flavonoids). The results indicated that quercetin enhanced Nrf2/HO-1 activity by increasing the phospho-p38MAPK expression in microglia cells exposed to LPS. The study suggested that quercetin regulated inflammatory responses in microglial cells and up-regulated HO-1 against LPS through MAPKs pathway^[64]. Systemic administration of LPS causes endotoxic shock by increasing the release of glutamate and NO production, iNOS expression, free radicals production, lipid peroxidation, and cytokine release as well as decreasing mitochondrial function. It was reported that quercetin prevented LPS-induced shock in rat brain. Quercetin (200mg/kg, IP) administration, 2 h before LPS injection, ameliorated increase in brain malondialdehyde (MDA), total nitrite/nitrate (NO(x)), as well as decrease in glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx). The study indicated the protective effects of quercetin on various systems related to oxidative stress and NO production in endotoxemic rat brain. The findings suggested quercetin may be effective treatment for septic shock by ameliorating the oxidative stress in brain during the early phase of endotoxic shock ^[65].

MPP+

MPP+ (1-Methyl-4-phenylpyridinium) with chemical formula C12H12N+ is a neurotoxic agents that disrupts the oxidative phosphorylation in mitochondria and leads to cell death selectively in dopaminergic neurons in the substantia nigra pars compacta. It is usually used for inducing Parkinson's disease in animal models. Lowy bodies are abnormal aggregates of proteins including alpha-synuclein, ubiquitin, neurofilament protein, alpha B crystallin and tau proteins in nerve cells. It was reported that antioxidants such as quercetin may be effective against MPP+-induced Parkinson's disease by incraesing the experssion of α-synuclein expression. Ahn et al., 2015 indicated that quercetin (100μM) prevented apoptosis and autophagy induced by MPP+ in PC12 cells by increasing α-synuclein expression. However, in knocking out α-synuclein has no considerable effect on cell survival^[66]. Quercetin (25 and 50 mg/kg, PO, for 14 days after the last injection of MPP+) ameliorated MPP+-caused behavioral abnormalities in rats by modulating the neurotransmitters (dopamine, serotonin, norepinephrine, glutamate, gamma-aminobutyric acid, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and homovanillic acid,), oxidative stress indices (MDA, NO and GSH) and inflammatory response (IL-1β, IL-6, and TNF-α) in the striatum^[67].

Streptozotocin:

Streptozotocin (STZ, 2-deoxy-2-(3-(methyl-3-nitrosoureido)-D-glucopyranose) is produced by Streptomycetes achromogenes that causes diabetes mellitus in animal models^[68]. Brain is very sensitive to hyperglycemia inuced by STZ and its complicatin is known as diabetic neuropathy^[68]. Oxidative stress has a vital role in the development of neurovascular complications in diabetes^[69-71]. Natural antioxidants such as quercetin can penetrate to blood brain barrier that may be effective against diabetic neuropathy. In this context, it was reported that quercetin (10 mg/kg/day ip for 14 days) has neuroprotection effects by modulating oxidative stress in the brain of STZ- diabetic rats^[72]. Quercetin (0.1%, PO, 27days) also exhibited neuroprotection effects by modulating lipoprotein receptor related protein (LRP1, regulator of glucose hemostasis and insulin signaling in the brain) and insulin signaling components (IRS1, PI3K and AKt1) as well as glucose transporters (GLUTs 1, 2, 3 and 4) in the brain of STZ-diabetic animals (MS et al., 2017). In diabetic neuropathic pain model, quercetin (100 mg/kg, PO, 4 weeks) increased nociceptive threshold in diabetic animals as noted by tail-immersion assay (warm water) Anjaneyulu and Chopra, 2003. Quercetin (10mg/kg, PO, for 4-weeks starting from the 4th week of STZ-administration) also ameliorated the cold allodynia as well as hyperalgesia in STZ-diabetic mice^[73]. Quercetin-loaded zein-based nanofibers ameliorated memory function in STZ-diabetic rats after which a crush injury of the right sciatic nerve. Quercetin (5-20mg/kg, PO, twice daily, 30days) in STZ-induced diabetic rats reversed the alteration in blood glucose, body weight, and performance in Morris water and elevated plus maze tasks. In addition, quercetin (40mg/kg, PO, twice daily) treatment during training trials (31-35days) significantly reduced escape latency and elevated time spent in target quadrant during Morris water maze task. The findings suggested that quercetin may be effective against cognitive dysfunction in diabetes^[74]. Quercetin (5%, 10% and 15%, PO, 21 days) improved the motor function of the sciatic nerve (large fibers) and nerve conduction velocity. Quercetin improved nerve regeneration and myelination via elevating the expression of pERK1/2 in the nerve of diabetic rats with nerve crush injury^[75]. In a diabetic retinopathy model, quercetin (50mg/kg, PO, 5 weeks) protected neurons by modulating oxidative stress, proapoptotic caspases and neurotrophic factors in the retina^[76].

Acrylamide:

Acrylamide (C3H5NO) is a white odorless crystalline industrial agent that is usually formed in foods containing carbohydrates and proteins during the heating process^[77]. It is recognized as neurotoxic agent. Acrylamide increased lipid peroxidation and also decreases the level of reduced glutathione (GSH) and antioxidant enzymes in brain. It was indicated quercetin ameliorated neurotoxicity induced by acrylamide in rats. Quercetin (5, 10, 20 and 40mg/kg, PO, for 3 days) prevented brain tissue against acrylamide by decreasing lipid peroxidation, and also increasing the levels of reduced GSH and antioxidant enzymes (SOD and CAT) in brain [78]. The other study indicated that injection of acrylamide (50 mg/kg) in rats increased dopamine, interferon-γ (IFN-) and 8-hydroxyguanosine as well as decreased serotonin content in the rat brain. However, Quercetin (10 mg/kg, IP, single dose before acrylamide injection) inhibited acrylamide-induced neurotoxicity as noted by decrease in the levels of dopamine, IFN- and 8-hydroxyguanosine and also increase in the levels serotonin. The findings indicated that quercetin may be an effective agent against acrylamide-induced neurotoxicity by modulating oxidative stress in brain^[79].

Galactose:

Galactose is a monosaccharide sugar that is suitable agent for induction of hyperglycemia in animal models ^[80]. It was reported that galacotse induces ROS production in the brain of rats. However, quercetin (400 mg/100 g diet, PO, 4 weeks) was effective against galactose-induced oxidative stress in brain as noted by decreas in the levels of malonaldehyde (MDA) and also increase in the levels of glutathione (GSH) and antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) in the brain. The findings sugsted that quercetin may be effective treatment against galactose-induced hyperglycemia and its complications^[81].

Glucose:

Quercetin protected neuronal PC12 cells against high-glucose by modulating oxidative stress indices, DNA fragmentation, Bax/Bcl-2 ratio, nuclear translocation of apoptosis-inducing factor, as well as poly(adenosine diphosphate [ADP]-ribose) polymerase cleavage. In addition, quercetin ameliorated caspase-3-dependent pathways as mechanisms of apoptotic death in neuronal cells exposed to glucose^[82].

Pentylenetetrazole:

Pentylenetetrazole (PTZ) is a selective blocker of the chloride channel coupled to the -aminobutyric acid type A (GABAA) receptor complex^[83] .It has been used as a circulatory and respiratory stimulant drug and also used in convulsive therapy. However, the side effect such as uncontrolled seizure limited its use. Recently, this agent is used for induction of seizure in animal models ^[83]. Quercetin (50 mg/kg, IP, before PTZ injection) ameliorated seizure severity from the onset of the kindling experiment by modulating oxidative stress in the hippocampi and cerebral cortices of kindled rats ^[83]. Sefil et al., 2014 also indicated that quercetin (10 and 20 mg/ kg, IP, 30 min before PTZ injection) delayed beginning of the seizure, decreased the seizure stage and duration^[84]. Quercetin (50 mg/kg, IP, for 7 days) elevated time to death of the animals received PTZ. In addition, quercetin (100 mg/kg) increased generalized tonic-colonic seizure beginning (GTCS) and decreased GTCS duration in mice injected by PTZ^[85]. Quercetin (10 mg/kg; 20 mg/kg; 40 mg/kg, p.o. for 15 days) with levetiracetam dose dependently improved depression related to epilepsy induced by PTZ in mice^[86].

Fluoride:

Fluoride is a natural mineral that leads to intoxication or fluorosis in human and experimental animals by inducing oxidative stress^[87]. Chronic exposure to fluoride intoxication may be associated with the occurrence of neurological disorders. Oxidative stress is recognized as a main mechanism involved in fluoride-induced central nervous systems injury. Antioxidants such as quercetin may be effective on fluoride induced brain damage. Pretreatment with quercetin (10 and 20 mg/kg, IP, 1 week) has a neuroprotective effects against fluoride by decreasing MDA content in brain and increasing the levels GSH, SOD and CAT in brain^[88].

Nitropropionic acid:

Nitropropionic acid (3-NP) is one of the toxic product that affects mitochondrial function. This toxin causes movement diseases such as dystonia^[89]. In the brain, 3-NP especially damages to the basal ganglia and causes Huntington's disease as noted by neurobehavioral deficit, motor deficits, pyknotic nuclei and astrogliosis in the striatum of rats^[89]. Decrease of mitochondrial respiratory, ATP content, and the levels of antioxidant as well as increase of oxidative stress in the brain have been recognized as mechanisms involved in the 3-NP toxicity^[89]. Quercetin supplementation (25 mg/kg, IP, 21days) ameliorated neurobehavioral deficits caused by 3-NP via modulating mitochondrial function and oxidative stress and in the brain of rats [89]. Study conducted by Denny Joseph and Muralidhara 2013 also confirmed that quercetin (25 mg/kg, PO 1h before 3-NP injection, 14 days) inhibited motor dysfunction by decreasing the levels of ROS, NO and MDA in rat model of Huntington's disease^[90]. Quercetin (25-50 mg/kg, IP, 6 h before and after 3-NP injection, 4 days) decreased serotonin metabolism that induced by 3-NP. Quercetin decreased microglial proliferation, and increased astrocyte numbers in the lesion core in animal exposed to 3-NP. The findings suggested that quercetin improved movement disturbances and anxiety in HD model by ameliorating inflammatory responses in brain^[91].

Rotenone:

Rotenone is one of the natural insecticides pesticide, and pesticide that is derived from some species of plants including Lonchocarpus, Derris, Tephrosia, and Mundulea^[92]. Rotenone is classified as a toxic agent for human and animal that its toxicity is noted by sign similar to those of Parkinson, dementia and depression diseases^[92]. Rotenone is a lipophilic agent that can penetrate into the blood–brain barrier and induces oxidative stress and apoptosis in dopaminergic neurons ^[92]. Oxidative stress is a main mechanism involved in the pathogenesis of neurodegenerative diseases. Quercetin liposomes (25 and 100 mg/kg, IP, 60 min before of rotenone injection) was effective against rotenone-induced neurotoxicity by ameliorating the activities of SOD, CAT, GPx and levels of MDA as wel as GSH content in the rats exposed to rotenone^[92]. Quercetin (25-75mg/kg, IP, at 12-h intervals for 4 days) attenuated rotenone-induced decrease in striatal dopamine, and GSH, as well as antioxidant enzymes (CAT and SOD) in dose-dependent manner. The modulating effects of quercetin on rotenone-induced NADH-diaphorase activity, noted to the possible implication of nitric oxide^[93]. Querceitn (25mg/kg, PO, 28 days) improved behavioral impairments in the rat exposed to rotenone by modulating oxidative response in brain regions, mitochondrial dysfunctions and striatal dopamine levels. Oxidative stress-mediated neurodegenerative diseases plays a main role in decrease of rotenone-induced neurotoxicity by quercetin^[94]. Autophagy is other mechanism has been involved in the rotenone-induced neurodegenerative diseases such as Parkinson's disease. It can induces endoplasmic reticulum (ER) stress and ER stress-caused apoptosis. Quercetin (50 mg/kg, IP, 4 weeks) ameliorated rotenone-induced behavioral impairment, augmented autophagy by inhibiting ER stress- induced apoptosis and oxidative stress in rat model^[95].

Acetic acid:

Acetic acid (CH3COOH) is a carboxylic acid that damages to various organs depend on the concentration ^[96]. This agent induces pain in animal model by induction of inflammation and oxidative stress in pain region^[96]. Quercetin ((3-100 mg/kg, IP, 30 min) before acetic acid injection) indicated its analgesic effect against acetic acid by decreasing inflammatory cytokines such as IL-1beta and increasing GSH levels. Inhibiting pro-nociceptive cytokine and the oxidative stress by querctin are the main factors in the improving inflammatory pain induced by acetic acid^[96].

Hydroxydopamine:

6-hydroxydopamine is a neurotoxic catecholaminergic that is used for induction Parkinson's disease in animal models. Quercetin (50 mg/kg, PO, 14 days) combated against 6-hydroxydopamine-induced neurotoxicity by inhibiting dopaminergic neuronal death and increasing the striatal dopamine levels as well as GSH and SOD in the striatum^[97]. Quercetin (30mg/kg, PO, 14 days) combated against 6-hydroxydopamine-induced oxidative stress in the striatum and dopaminergic neuronal death in the rat model of PD [98]. It was indicated that quercetin metabolites protected neuronal cells against 6-hydroxydopamine after glucuronidation. Quercetin aglycone suppressed 6-OHDA-induced H₂O₂ production and cell death in mouse neuroblastoma^[99].

DISCUSSION:

Oxidative stress play a main role in the pathogenesis of several diseases^[100-108]. Recent years, natural products are considered for treatment of various diseases because of main activities such as antioxidant eﬀects^[109-117]. Chemical and natural toxic agents cause toxicity in human and animal following chronic exposure or high doses. However, quercetin could protect nervous system against their toxicities. Several studies have suggested that quercetin decreased neurotoxicity via modulating oxidative stress, inflammation, and apoptosis. According to the results of several important investigations, quercetin acts as an antidote in different intoxications induced by natural toxins. However, clinical trial studies should be done to confirm the efficacy and safety of quercetin for improving neurodegenerative diseases in human.

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43. Samarghandian S, Borji A, Afshari R, Delkhosh MB, gholami A. The effect of lead acetate on oxidative stress and antioxidant status in rat bronchoalveolar lavage fluid and lung tissue. Toxicol Mech Methods. 23(6):2013; 432-6.

44. Samarghandian S, Azimi-Nezhad M, Farkhondeh T, Samini F. Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney. Biomed Pharmacother. 87:2017; 223-229.

45. Farkhondeh T, Samarghandian S, Sadighara P. Lead exposure and asthma: An overview of observational and experimental studies. Toxin Reviews. 34:2015; 6-10

46. Liu CM1, Zheng GH, Cheng C, Sun JM. Quercetin protects mouse brain against lead-induced neurotoxicity. J Agric Food Chem. 61(31):2013; 7630-5.

47. Samarghandia, S, Azimi-Nezhad M, Shabestari MM, Azad FJd, Farkhondeh T, Bafandeh F. Effect of chronic exposure to cadmium on serum lipid, lipoprotein and oxidative stress indices in male rats. Interdisciplinary Toxicology. 8(3): 2015; 151-154

48. Shaterzadeh-Yazdi H, Noorbakhsh MF, Hayati F, Samarghandian S, Farkhondeh T. Immunomodulatory and anti-inflammatory effects of thymoquinone. Cardiovasc Hematol Disord Drug Targets. 18(1):2018; 52-60.

49. Ben Mimouna S, Chemek M, Boughammoura S, Haouas Z, Messaoudi I.Protective role of zinc against the neurotoxicity induced by exposure to cadmium during gestation and lactation periods on hippocampal volume of pups tested in early adulthood. Drug Chem Toxicol. 2018:1-10. doi: 10.1080/01480545.2018.1461901.

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53. Abdalla FH, Schmatz R, Cardoso AM, Carvalho FB, Baldissarelli J, de Oliveira JS, Rosa MM, Gonçalves Nunes MA, Rubin MA, da Cruz IB, Barbisan F, Dressler VL, Pereira LB, Schetinger MR, Morsch VM, Gonçalves JF, Mazzanti CM. Quercetin protects the impairment of memory and anxiogenic-like behavior in rats exposed to cadmium: Possible involvement of the acetylcholinesterase and Na(+),K(+)-ATPase activities. Physiol Behav. 135:2014; 152-67.

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55. Kanter M, Unsal C, Aktas C, Erboga M.Neuroprotective effect of quercetin against oxidative damage and neuronal apoptosis caused by cadmium in hippocampus. Toxicol Ind Health. 32(3):2016; 541-50.

56. Halder S, Kar R, Galav V, Mehta AK, Bhattacharya SK, Mediratta PK, Banerjee BD. Cadmium exposure during lactation causes learning and memory-impairment in F1 generation mice: amelioration by quercetin. Drug Chem Toxicol. 39(3):2016; 272-8.

57. Gupta R, Shukla RK, Chandravanshi LP, Srivastava P, Dhuriya YK, Shanker J, Singh MP, Pant AB, Khanna VK. Protective role of quercetin in cadmium-induced cholinergic dysfunctions in rat brain by modulating mitochondrial integrity and MAP kinase signaling. Mol Neurobiol. 54(6):2017; 4560-4583.

58. Gupta R, Shukla RK, Pandey A, Sharma T, Dhuriya YK, Srivastava P, Singh MP, Siddiqi MI, Pant AB, Khanna VK. Involvement of PKA/DARPP-32/PP1α and β- arrestin/Akt/GSK-3β signaling in cadmium-induced DA-D2 receptor-mediated motor dysfunctions: Sci Rep. 8(1):2018; 2528.

59. Ghosh A, Mandal AK, Sarkar S, Panda S, Das N. Nanoencapsulation of quercetin enhances its dietary efficacy in combating arsenic-induced oxidative damage in liver and brain of rats. Life Sci. 84(3-4):2009; 75-80.

60. Halder S, Kar R, Mehta AK, Bhattacharya SK, Mediratta PK, Banerjee BD. Quercetin modulates the effects of Chromium exposure on learning, Memory and Antioxidant Enzyme Activity in F1 Generation Mice. Biol Trace Elem Res. 171(2):2016; 391-398.

61. Nday CM, Halevas E, Jackson GE, Salifoglou A.Quercetin encapsulation in modified silica nanoparticles: potential use against Cu(II)-induced oxidative stress in neurodegeneration. J Inorg Biochem. 145:2015; 51-64.

62. Farkhondeh T, Samarghandian S, Samini F. Antidotal effects of curcumin against neurotoxic agents: An updated review. Asian Pac J Trop Med. 9(10):2016; 947-953.

63. Kao TK1, Ou YC, Raung SL, Lai CY, Liao SL, Chen CJ. Inhibition of nitric oxide production by quercetin in endotoxin/cytokine-stimulated microglia. Life Sci. 86(9-10):2010; 315-21.

64. Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A. Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One. 10(10):2015; e0141509.

65. Abd El-Gawad HM, Khalifa AE. Quercetin, coenzyme Q10, and L-canavanine as protective agents against lipid peroxidation and nitric oxide generation in endotoxin-induced shock in rat brain. Pharmacol Res. 43(3):2001; 257-63.

66. Ahn TB, Jeon BS. The role of quercetin on the survival of neuron-like PC12 cells and the expression of α-synuclein. Neural Regen Res. 10(7):2015; 1113-9.

67. Singh S, Jamwal S, Kumar P. Neuroprotective potential of Quercetin in combination with piperine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. Neural Regen Res. 12(7):2017; 1137-1144.

68. Farkhondeh T, Samarghandian S, Borji A. An overview on cardioprotective and anti-diabetic effects of thymoquinone. Asian Pac J Trop Med. 10(9):2017; 849-854.

69. Samarghandian S, Afshari R, Farkhondeh T. Effect of long-term treatment of morphine on enzymes, oxidative stress indices and antioxidant status in male rat liver. Int J Clin Exp Med. 7(5):2014; 1449-53.

70. Moghaddam HS, Samarghandian S, Farkhondeh T. Effect of bisphenol A on blood glucose, lipid profile and oxidative stress indices in adult male mice. Toxicol Mech Methods. 25(7):2015; 507-13.

71. Samarghandian S, Azimi-Nezhad M, Afshari R, Farkhondeh T, Karimnezhad F. Effects of buprenorphine on balance of oxidant/antioxidant system in the different ages of male rat liver. J Biochem Mol Toxicol. 29(6):2015; 249-53.

72. Coldiron AD Jr, Sanders RA, Watkins JB 3rd. Effects of combined quercetin and coenzyme Q(10) treatment on oxidative stress in normal and diabetic rats. J Biochem Mol Toxicol. 16(4):2002; 197-202.

73. Anjaneyulu M, Chopra K. Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol. 31(4):2004; 244-8.

74. Bhutada P, Mundhada Y, Bansod K, Bhutada C, Tawari S, Dixit P, Mundhada D. Ameliorative effect of quercetin on memory dysfunction in streptozotocin-induced diabetic rats. Neurobiol Learn Mem. 94(3):2010; 293-302.

75. Thipkaew C, Wattanathorn J, Muchimapura S. Electrospun nanofibers loaded with quercetin promote the recovery of focal entrapment neuropathy in a rat model of streptozotocin-induced diabetes. Biomed Res Int. 2017;2017:2017493.

76. Ola MS, Ahmed MM, Shams S, Al-Rejaie SS. Neuroprotective effects of quercetin in diabetic rat retina. Saudi J Biol Sci. 24(6):2017; 1186-1194.

77. Samarghandian S, Farkhondeh T, Azimi-Nezhad M. Protective effects of chrysin against drugs and toxic agents. Dose Response. 15(2):2017; 1559325817711782.

78. Uthra C, Shrivastava S, Jaswal A, Sinha N, Reshi MS, Shukla S. Therapeutic potential of quercetin against acrylamide induced toxicity in rats. Biomed Pharmacother. 86:2017; 705-714.

79. Zargar S, Siddiqi NJ, Ansar S, Alsulaimani MS, El Ansary AK. Therapeutic role of quercetin on oxidative damage induced by acrylamide in rat brain. Pharm Biol. 54(9):2016; 1763-7.

80. Farkhondeh T, Samarghandian S. Antidotal effects of curcumin against agents-induced cardiovascular toxicity. Cardiovasc Hematol Disord Drug Targets. 16(1):2016; 30-37.

81. Ramana BV, Kumar VV, Krishna PN, Kumar CS, Reddy PU, Raju TN. Effect of quercetin on galactose-induced hyperglycaemic oxidative stress in hepatic and neuronal tissues of Wistar rats. Acta Diabetol. 43(4):2006; 135-41.

82. Bournival J, Francoeur MA, Renaud J, Martinoli MG. Quercetin and sesamin protect neuronal PC12 cells from high-glucose-induced oxidation, nitrosative stress, and apoptosis. Rejuvenation Res. 15(3):2012; 322-33.

83. Nassiri-Asl M, Moghbelinejad S, Abbasi E, Yonesi F, Haghighi MR, Lotfizadeh M, Bazahang P. Effects of quercetin on oxidative stress and memory retrieval in kindled rats. Epilepsy Behav. 28(2):2013; 151-5.

84. Sefil F, Kahraman I, Dokuyucu R, Gokce H, Ozturk A, Tutuk O, Aydin M, Ozkan U, Pinar N. Ameliorating effect of quercetin on acute pentylenetetrazole induced seizures in rats. Int J Clin Exp Med. 7(9):2014; 2471-7.

85. Nassiri-Asl M, Hajiali F, Taghiloo M, Abbasi E, Mohseni F, Yousefi F. Comparison between the effects of quercetin on seizure threshold in acute and chronic seizure models. Toxicol Ind Health. 32(5):2016; 936-44.

86. Singh T, Kaur T, Goel RK. Adjuvant quercetin therapy for combined treatment of epilepsy and comorbid depression. Neurochem Int. 104:2017; 27-33.

87. Farkhondeh t, Samarghandian S. The hepatoprotective effects of curcumin against drugs and toxic agents: an updated review. Toxin Reviews. 35( 3-4): 2016; 133-140

88. Nabavi SF, Nabavi SM, Latifi AM, Mirzaei M, Habtemariam S, Moghaddam AH. Mitigating role of quercetin against sodium fluoride-induced oxidative stress in the rat brain. Pharm Biol. 50(11):2012; 1380-3.

89. Sandhir R, Mehrotra A. Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: implications in Huntington's disease. Biochim Biophys Acta. 1832(3):2013; 421-30.

90. Denny Joseph KM, Muralidhara. Enhanced neuroprotective effect of fish oil in combination with quercetin against 3-nitropropionicacid induced oxidative stress in rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 40:2013; 83-92.

91. Chakraborty J, Singh R, Dutta D, Naskar A, Rajamma U, Mohanakumar KP. Quercetin improves behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3-nitropropionic acid-induced rat model of Huntington's Disease. CNS Neurosci Ther. 20(1):2014; 10-9.

92. Sánchez-Reus MI, Gómez del Rio MA, Iglesias I, Elorza M, Slowing K, Benedí J. Standardized Hypericum perforatum reduces oxidative stress and increases gene expression of antioxidant enzymes on rotenone-exposed rats. Neuropharmacology. 52(2):2007; 606-16.

93. Karuppagounder SS, Madathil SK, Pandey M, Haobam R, Rajamma U, Mohanakumar KP. Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson's disease in rats. Neuroscience. 236:2013; 136-48.

94. Denny Joseph KM, Muralidhara. Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson's disease. Neurochem Res.40(5): 2015; 894-905.

95. El-Horany HE, El-Latif RN, ElBatsh MM, Emam MN. Ameliorative effect of quercetin on neurochemical and behavioral deficits in rotenone rat model of Parkinson's Disease: modulating autophagy (Quercetin on Experimental Parkinson's Disease). J Biochem Mol Toxicol. 30(7):2016; 360-9.

96. Valério DA, Georgetti SR, Magro DA, Casagrande R, Cunha TM, Vicentini FT, Vieira SM, Fonseca MJ, Ferreira SH, Cunha FQ, Verri WA Jr. Quercetin reduces inflammatory pain: inhibition of oxidative stress and cytokine production. J Nat Prod. 72(11):2009; 1975-9.

97. Haleagrahara N1, Siew CJ, Ponnusamy K. Effect of quercetin and desferrioxamine on 6-hydroxydopamine (6-OHDA) induced neurotoxicity in striatum of rats. J Toxicol Sci. 38(1):2013; 25-33.

98. Haleagrahara N, Siew CJ, Mitra NK, Kumari M. Neuroprotective effect of bioflavonoid quercetin in 6-hydroxydopamine-induced oxidative stress biomarkers in the rat striatum. Neurosci Lett. 500(2):2011; 139-43.

99. Mukai R, Kawabata K, Otsuka S, Ishisaka A, Kawai Y, Ji ZS, Tsuboi H, Terao J. Effect of quercetin and its glucuronide metabolite upon 6-hydroxydopamine-induced oxidative damage in Neuro-2a cells. Free Radic Res. 46(8):2012; 1019-28.

100. Farkhondeh T, Samarghandian S, Azimi-Nezhad M. The effect of lead exposure on some inflammatory biomarkers of lung lavage fluid in rats. Toxin Rev.36(2); 2017: 161-164.

101. Samarghandian S, Shibuya M. Vascular Endothelial Growth Factor Receptor Family in Ascidians, Halocynthia roretzi (Sea Squirt). Its High Expression in Circulatory System-Containing Tissues. Int J Mol Sci. 14(3):2013; 4841-53.

102. Samarghandian S, Azimini-Nezhad M, Farkhondeh T. The Effects of Zataria Multiflora on blood glucose, lipid profile and oxidative stress parameters in adult mice during exposure to bisphenol A. Cardiovasc Hematol Disord Drug Targets. 16(1):2016; 41-46.

103. Samarghandian S, Azimi-Nezhad M, Borji A, Farkhondeh T. Crocus sativus L. (saffron) extract reduces the extent of oxidative stress and proinflammatory state in aged rat kidney. Prog Nutr. 18(3); 2016: 299-310

104. Samarghandian S, Farkhondeh T, Samini F, Borji A. Protective effects of carvacrol against oxidative stress induced by chronic stress in rat's brain, liver, and kidney. Biochem Res Int. 2016;2016:2645237.

105. Samarghandian S, Azimi-Nezhad M, Samini F. Preventive effect of safranal against oxidative damage in aged male rat brain. Exp Anim. 64(1):2015; 65-71.

106. Samarghandian S, Azimi-Nezhad M, Samini F. Ameliorative effect of saffron aqueous extract on hyperglycemia, hyperlipidemia, and oxidative stress on diabetic encephalopathy in streptozotocin induced experimental diabetes mellitus. Biomed Res Int. 2014;2014:920857.

107. Samarghandian S, Borji A. Anticarcinogenic effect of saffron (Crocus sativus L.) and its ingredients. Pharmacognosy Res. 6(2):2014; 99-107.

108. Samarghandian S, Nezhad MA, Mohammadi G. Role of caspases, Bax and Bcl-2 in chrysin-induced apoptosis in the A549 human lung adenocarcinoma epithelial cells. Anticancer Agents Med Chem. 14(6):2014; 901-9.

109. Samarghandian S, Borji A, Delkhosh MB, Samini F. Safranal treatment improves hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats. J Pharm Pharm Sci. 16(2):2013; 352-62.

110. Samarghandian S, Shabestari MM. DNA fragmentation and apoptosis induced by safranal in human prostate cancer cell line. Indian J Urol. 29(3):2013; 177-83.

111. Farahmand SK, Samini F, Samini M, Samarghandian S. Safranal ameliorates antioxidant enzymes and suppresses lipid peroxidation and nitric oxide formation in aged male rat liver. Biogerontology. 14(1):2013; 63-71.

112. Samini F, Samarghandian S, Borji A, Mohammadi G, bakaian M. Curcumin pretreatment attenuates brain lesion size and improves neurological function following traumatic brain injury in the rat. Pharmacol Biochem Behav. 110:2013; 238-44.

113. Samarghandian S, Afshari JT, Davoodi S. Chrysin reduces proliferation and induces apoptosis in the human prostate cancer cell line pc-3. Clinics (Sao Paulo). 66(6):2011; 1073-9.

114. Samarghandian S1, Tavakkol Afshari J, Davoodi S. Suppression of pulmonary tumor promotion and induction of apoptosis by Crocus sativus L. extraction. Appl Biochem Biotechnol. 164(2):2011; 238-47.

115. Samarghandian S, Afshari JT, Davoodi S. Honey induces apoptosis in renal cell carcinoma. Pharmacogn Mag. 7(25):2011; 46-52.

116. Samarghandian S, Ohata H, Yamauchi N, Shibasaki T. Corticotropin-releasing factor as well as opioid and dopamine are involved in tail-pinch-induced food intake of rats. Neuroscience. 116(2):2003; 519-24.

117. Koike K, Shinozawa Y, Yamazaki M, Endo T, Nomura R, Aiboshi J, Samarghandian S, Emmett M, Peterson VM. Recombinant human interleukin-1alpha increases serum albumin, Gc-globulin, and alpha1-antitrypsin levels in burned mice. Tohoku J Exp Med. 198(1):2002; 23-9.

Received on 05.06.2018 Modified on 17.07.2018

Research J. Pharm. and Tech 2019; 12(2):561-568.

DOI: 10.5958/0974-360X.2019.00100.8