Abstract
Parkinson’s disease (PD) is currently the second most common neurodegenerative disease, being characterized by motor and non-motor symptoms. The therapeutic options available for its treatment are limited, do not slow the progression of the disease, and have serious side effects. For this reason, many studies have sought to find compounds with neuroprotective properties that bring additional benefits to current therapy. In this context, resveratrol is a phenolic compound, found in many plant species, capable of crossing the blood–brain barrier and having multiple biological properties. Experimental studies in vitro and in vivo have shown that it can prevent or slow the progression of a variety of diseases, including PD. In this systematic review, we summarize the effects of resveratrol in experimental in vivo and in vitro models of PD and discuss the molecular mechanisms involved in its action. The bibliographic search was performed in the databases of PubMed, Web of Science, SciELO, and Google Scholar, and based on the inclusion criteria, 41 articles were selected and discussed. Most of the included studies have demonstrated neuroprotective effects of resveratrol. In general, resveratrol prevented behavioral and/or neurological disorders, improved antioxidant defenses, reduced neuroinflammatory processes, and inhibited apoptosis. In summary, this systematic review offers important scientific evidence of neuroprotective effects of resveratrol in PD and also provide valuable information about its mechanism of action that can support future clinical studies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abolaji AO, Adedara AO, Adie MA et al (2018) Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster. Biochem Biophys Res Commun 503:1042–1048. https://doi.org/10.1016/j.bbrc.2018.06.114
Albani D, Polito L, Batelli S et al (2009) The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1–42) peptide. J Neurochem 110:1445–1456. https://doi.org/10.1111/j.1471-4159.2009.06228.x
Allen Reish HE, Standaert DG (2015) Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis 5:1–19. https://doi.org/10.3233/JPD-140491
Alvira D, Yeste-Velasco M, Folch J et al (2007) Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 147:746–756. https://doi.org/10.1016/j.neuroscience.2007.04.029
Anandhan A, Tamilselvam K, Vijayraja D et al (2010) Resveratrol attenuates oxidative stress and improves behaviour in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenged parkinsonic mice. Ann Neurosci. https://doi.org/10.5214/ans.0972-7531.1017304
Arbo BD, André-Miral C, Nasre-Nasser RG et al (2020) Resveratrol derivatives as potential treatments for Alzheimer’s and Parkinson’s disease. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2020.00103
Bagatini PB, Saur L, Rodrigues MF et al (2011) The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis. Invertebr Neurosci 11:43–51. https://doi.org/10.1007/s10158-011-0116-3
Balestrino R, Schapira AHV (2020) Parkinson disease. Eur J Neurol 27:27–42. https://doi.org/10.1111/ene.14108
Battelli MG, Polito L, Bortolotti M, Bolognesi A (2016) Xanthine oxidoreductase-derived reactive species: physiological and pathological effects. Oxid Med Cell Longev 2016:1–8. https://doi.org/10.1155/2016/3527579
Bellinger FP, Bellinger MT, Seale LA et al (2011) Glutathione peroxidase 4 is associated with neuromelanin in substantia nigra and dystrophic axons in putamen of Parkinson’s brain. Mol Neurodegener 6:8. https://doi.org/10.1186/1750-1326-6-8
Bender A, Krishnan KJ, Morris CM et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517. https://doi.org/10.1038/ng1769
Bernard D, Prasanth KV, Tripathi V et al (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J 29:3082–3093. https://doi.org/10.1038/emboj.2010.199
Blanchet J, Longpré F, Bureau G et al (2008) Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuro-Psychopharmacology Biol Psychiatry 32:1243–1250. https://doi.org/10.1016/j.pnpbp.2008.03.024
Boocock DJ, Faust GES, Patel KR et al (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev. https://doi.org/10.1158/1055-9965.EPI-07-0022
Bose A, Beal MF (2016) Mitochondrial dysfunction in Parkinson’s disease. J Neurochem 139:216–231. https://doi.org/10.1111/jnc.13731
Bøttger P, Tracz Z, Heuck A et al (2011) Distribution of Na/K-ATPase alpha 3 isoform, a sodium-potassium P-type pump associated with rapid-onset of dystonia parkinsonism (RDP) in the adult mouse brain. J Comp Neurol 519:376–404. https://doi.org/10.1002/cne.22524
Bournival J, Quessy P, Martinoli M-G (2009) Protective effects of resveratrol and quercetin against mPP+-induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neurons. Cell Mol Neurobiol 29:1169–1180. https://doi.org/10.1007/s10571-009-9411-5
Burbulla LF, Song P, Mazzulli JR et al (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357(6357):1255–1261. https://doi.org/10.1126/science.aam9080
Calamini B, Ratia K, Malkowski MG et al (2010) Pleiotropic mechanisms facilitated by resveratrol and its metabolites. Biochem J 429:273–282. https://doi.org/10.1042/BJ20091857
Chandra G, Roy A, Rangasamy SB, Pahan K (2017) Induction of adaptive immunity leads to nigrostriatal disease progression in MPTP mouse model of Parkinson’s disease. J Immunol 198:4312–4326. https://doi.org/10.4049/jimmunol.1700149
Chang CY, Choi D-K, Lee DK et al (2013) Resveratrol confers protection against rotenone-induced neurotoxicity by modulating myeloperoxidase levels in glial cells. PLoS One 8:e60654. https://doi.org/10.1371/journal.pone.0060654
Chao J, Li H, Cheng K-W et al (2010) Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. J Nutr Biochem 21:482–489. https://doi.org/10.1016/j.jnutbio.2009.02.004
Chao J, Yu M-S, Ho Y-S et al (2008) Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic Biol Med 45:1019–1026. https://doi.org/10.1016/j.freeradbiomed.2008.07.002
Chen SF, Hsu CW, Huang WH, Wang JY (2008) Post-injury baicalein improves histological and functional outcomes and reduces inflammatory cytokines after experimental traumatic brain injury. Br J Pharmacol. https://doi.org/10.1038/bjp.2008.345
Choi D-H, Cristóvão AC, Guhathakurta S et al (2012) NADPH oxidase 1-mediated oxidative stress leads to dopamine neuron death in Parkinson’s disease. Antioxid Redox Signal 16:1033–1045. https://doi.org/10.1089/ars.2011.3960
Cicchetti F, Drouin-Ouellet J, Gross RE (2009) Environmental toxins and Parkinson’s disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci 30:475–483. https://doi.org/10.1016/j.tips.2009.06.005
Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease. JAMA 311:1670. https://doi.org/10.1001/jama.2014.3654
Croisier E, Moran LB, Dexter DT et al (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2:14. https://doi.org/10.1186/1742-2094-2-14
D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor signaling during peripheral organ inflammation. J Neurosci 29:2089–2102. https://doi.org/10.1523/JNEUROSCI.3567-08.2009
da Rocha Lindner G, Bonfanti Santos D, Colle D et al (2015) Improved neuroprotective effects of resveratrol-loaded polysorbate 80-coated poly(lactide) nanoparticles in MPTP-induced Parkinsonism. Nanomedicine 10:1127–1138. https://doi.org/10.2217/nnm.14.165
Dickson DW (2012) Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a009258
Enogieru AB, Omoruyi SI, Hiss DC, Ekpo OE (2019) GRP78/BIP/HSPA5 as a therapeutic target in models of parkinson’s disease: a mini review. Adv Pharmacol Sci 2019:1–11. https://doi.org/10.1155/2019/2706783
Erekat NS (2018) Apoptosis and its role in Parkinson’s disease. In: Parkinson’s disease: pathogenesis and clinical aspects. Codon Publications, pp 65–82 https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch4
Falquetto B, Thieme K, Malta MB et al (2020) Oxidative stress in the medullary respiratory neurons contributes to respiratory dysfunction in the 6-OHDA model of Parkinson’s disease. J Physiol 598:5271–5293. https://doi.org/10.1113/JP279791
Felger JC, Treadway MT (2017) Inflammation effects on motivation and motor activity: role of dopamine. Neuropsychopharmacology 42:216–241. https://doi.org/10.1038/npp.2016.143
Feng N, Jia Y, Huang X (2019) Exosomes from adipose-derived stem cells alleviate neural injury caused by microglia activation via suppressing NF-kB and MAPK pathway. J Neuroimmunol. https://doi.org/10.1016/j.jneuroim.2019.576996
Feng Y, Liu T, Dong S-Y et al (2015) Rotenone affects p53 transcriptional activity and apoptosis via targeting SIRT1 and H3K9 acetylation in SH-SY5Y cells. J Neurochem 134:668–676. https://doi.org/10.1111/jnc.13172
Fifel K (2017) Alterations of the circadian system in Parkinson’s disease patients. Mov Disord 32:682–692. https://doi.org/10.1002/mds.26865
Filograna R, Godena VK, Sanchez-Martinez A et al (2016) Superoxide dismutase (SOD)-mimetic M40403 is protective in cell and fly models of paraquat toxicity. J Biol Chem 291:9257–9267. https://doi.org/10.1074/jbc.M115.708057
Fu R, Luo X-G, Ren Y et al (2016) Clinical characteristics of fatigued Parkinson’s patients and the response to dopaminergic treatment. Transl Neurodegener 5:9. https://doi.org/10.1186/s40035-016-0056-2
Gaballah HH, Zakaria SS, Elbatsh MM, Tahoon NM (2016) Modulatory effects of resveratrol on endoplasmic reticulum stress-associated apoptosis and oxido-inflammatory markers in a rat model of rotenone-induced Parkinson’s disease. Chem Biol Interact 251:10–16. https://doi.org/10.1016/j.cbi.2016.03.023
Gaki GS, Papavassiliou AG (2014) Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson’s disease. NeuroMolecular Med 16:217–230. https://doi.org/10.1007/s12017-014-8294-x
Gardaneh M, Gholami M, Maghsoudi N (2011) Synergy between glutathione peroxidase-1 and astrocytic growth factors suppresses free radical generation and protects dopaminergic neurons against 6-hydroxydopamine. Rejuvenation Res 14:195–204. https://doi.org/10.1089/rej.2010.1080
Gélinas S, Martinoli M-G (2002) Neuroprotective effect of estradiol and phytoestrogens on MPP + -induced cytotoxicity in neuronal PC12 cells. J Neurosci Res 70:90–96. https://doi.org/10.1002/jnr.10315
Gerhardt E, Gräber S, Szegő ÉM et al (2011) Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. PLoS One 6:e28855. https://doi.org/10.1371/journal.pone.0028855
Guo Y-J, Dong S-Y, Cui X-X et al (2016) Resveratrol alleviates MPTP-induced motor impairments and pathological changes by autophagic degradation of α-synuclein via SIRT1-deacetylated LC3. Mol Nutr Food Res 60:2161–2175. https://doi.org/10.1002/mnfr.201600111
Han Y-S, Zheng W-H, Bastianetto S et al (2004) Neuroprotective effects of resveratrol against β -amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol 141:997–1005. https://doi.org/10.1038/sj.bjp.0705688
Hemmati-Dinarvand M, Saedi S, Valilo M et al (2019) Oxidative stress and Parkinson’s disease: conflict of oxidant-antioxidant systems. Neurosci Lett 709:134296. https://doi.org/10.1016/j.neulet.2019.134296
Henderson MX, Trojanowski JQ, Lee VM-Y (2019) α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies. Neurosci Lett 709:134316. https://doi.org/10.1016/j.neulet.2019.134316
Hooijmans CR, Rovers MM, de Vries RB et al (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14:43. https://doi.org/10.1186/1471-2288-14-43
Hou Y, Wang K, Wan W et al (2018) Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats. Genes Dis 5:245–255. https://doi.org/10.1016/j.gendis.2018.06.001
Hu LW, Yen JH, Shen YT et al (2014) Luteolin modulates 6-hydroxydopamine-induced transcriptional changes of stress response pathways in PC12 cells. PLoS One. https://doi.org/10.1371/journal.pone.0097880
Hu X, Zhang D, Pang H et al (2008) Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. J Immunol 181:7194–7204. https://doi.org/10.4049/jimmunol.181.10.7194
Hu Z-L, Sun T, Lu M et al (2019) Kir6.1/K-ATP channel on astrocytes protects against dopaminergic neurodegeneration in the MPTP mouse model of Parkinson’s disease via promoting mitophagy. Brain Behav Immun 81:509–522. https://doi.org/10.1016/j.bbi.2019.07.009
Huang N, Zhang Y, Chen M et al (2019) Resveratrol delays 6-hydroxydopamine-induced apoptosis by activating the PI3K/Akt signaling pathway. Exp Gerontol 124:110653. https://doi.org/10.1016/j.exger.2019.110653
Iovino L, Tremblay ME, Civiero L (2020) Glutamate-induced excitotoxicity in Parkinson’s disease: The role of glial cells. J Pharmacol Sci 144:151–164. https://doi.org/10.1016/j.jphs.2020.07.011
Ji Q, Liu X, Han Z et al (2015) Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer 15:97. https://doi.org/10.1186/s12885-015-1119-y
Jin F, Wu Q, Lu Y-F et al (2008) Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur J Pharmacol 600:78–82. https://doi.org/10.1016/j.ejphar.2008.10.005
Joe E-H, Choi D-J, An J et al (2018) Astrocytes, microglia, and Parkinson’s disease. Exp Neurobiol 27:77–87. https://doi.org/10.5607/en.2018.27.2.77
Johnson JJ, Nihal M, Siddiqui IA et al (2011) Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.201100117
Jose S, Anju SS, Cinu TA et al (2014) In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery. Int J Pharm 474:6–13. https://doi.org/10.1016/j.ijpharm.2014.08.003
Kam T-I, Hinkle JT, Dawson TM, Dawson VL (2020) Microglia and astrocyte dysfunction in parkinson’s disease. Neurobiol Dis 144:105028. https://doi.org/10.1016/j.nbd.2020.105028
Kanthasamy K, Gordon R, Jin H et al (2011) Neuroprotective effect of resveratrol against methamphetamine-induced dopaminergic apoptotic cell death in a cell culture model of neurotoxicity. Curr Neuropharmacol 9:49–53. https://doi.org/10.2174/157015911795017353
Karuppagounder SS, Madathil SK, Pandey M et al (2013) Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson’s disease in rats. Neuroscience. https://doi.org/10.1016/j.neuroscience.2013.01.032
Kaspar JW, Niture SK, Jaiswal AK (2009) Nrf 2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 47:1304–1309. https://doi.org/10.1016/j.freeradbiomed.2009.07.035
Khan MM, Ahmad A, Ishrat T et al (2010) Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res 1328:139–151. https://doi.org/10.1016/j.brainres.2010.02.031
Kim J, Min K-J, Seol W et al (2010) Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses. J Neurochem 115:1161–1171. https://doi.org/10.1111/j.1471-4159.2010.07004.x
Kim S, Indu Viswanath AN, Park J-H et al (2020) Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson’s disease animal model. Neuropharmacology 167:107989. https://doi.org/10.1016/j.neuropharm.2020.107989
Lee FJS, Liu F (2008) Genetic factors involved in the pathogenesis of Parkinson’s disease. Brain Res Rev 58:354–364. https://doi.org/10.1016/j.brainresrev.2008.02.001
Lee H-J, Suk J-E, Patrick C et al (2010) Direct transfer of α-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272. https://doi.org/10.1074/jbc.M109.081125
Lee MK, Kang SJ, Poncz M et al (2007) Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med 39:376–384. https://doi.org/10.1038/emm.2007.42
Leggio L, Vivarelli S, L’Episcopo F et al (2017) microRNAs in Parkinson’s disease: from pathogenesis to novel diagnostic and therapeutic approaches. Int J Mol Sci 18:2698. https://doi.org/10.3390/ijms18122698
Li J, Zhang C-X, Liu Y-M et al (2017) A comparative study of anti-aging properties and mechanism: resveratrol and caloric restriction. Oncotarget 8:65717–65729. https://doi.org/10.18632/oncotarget.20084
Lin K-L, Lin K-J, Wang P-W et al (2018) Resveratrol provides neuroprotective effects through modulation of mitochondrial dynamics and ERK1/2 regulated autophagy. Free Radic Res 52:1371–1386. https://doi.org/10.1080/10715762.2018.1489128
Lin T-K, Chen S-D, Chuang Y-C et al (2014) Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci 15:1625–1646. https://doi.org/10.3390/ijms15011625
Lin Y, Chen F, Zhang J et al (2013) Neuroprotective effect of resveratrol on ischemia/reperfusion injury in rats through TRPC6/CREB pathways. J Mol Neurosci 50:504–513. https://doi.org/10.1007/s12031-013-9977-8
Liu Q, Zhu D, Jiang P et al (2019) Resveratrol synergizes with low doses of L-DOPA to improve MPTP-induced Parkinson disease in mice. Behav Brain Res 367:10–18. https://doi.org/10.1016/j.bbr.2019.03.043
Liu Z, Yu Y, Li X et al (2011) Curcumin protects against A53T alpha-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol Res. https://doi.org/10.1016/j.phrs.2011.01.004
Lofrumento DD, Nicolardi G, Cianciulli A et al (2014) Neuroprotective effects of resveratrol in an MPTP mouse model of Parkinson’s-like disease: Possible role of SOCS-1 in reducing pro-inflammatory responses. Innate Immun 20:249–260. https://doi.org/10.1177/1753425913488429
Lohr KM, Bernstein AI, Stout KA et al (2014) Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proc Natl Acad Sci 111:9977–9982. https://doi.org/10.1073/pnas.1402134111
Lu D-L, Ding D-J, Yan W-J et al (2013) Influence of glucuronidation and reduction modifications of resveratrol on its biological activities. ChemBioChem 14:1094–1104. https://doi.org/10.1002/cbic.201300080
Lu K-T, Ko M-C, Chen B-Y et al (2008) Neuroprotective effects of resveratrol on MPTP-induced neuron loss mediated by free radical scavenging. J Agric Food Chem 56:6910–6913. https://doi.org/10.1021/jf8007212
Luchs A, Pantaleão C (2010) Apoptosis and in vivo models to study the molecules related to this phenomenon. Einstein (São Paulo) 8:495–497. https://doi.org/10.1590/s1679-45082010rb1685
Maguire-Zeiss KA, Short DW, Federoff HJ (2005) Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson’s disease? Mol Brain Res 134:18–23. https://doi.org/10.1016/j.molbrainres.2004.09.014
Maitra U, Scaglione MN, Chtarbanova S, O’Donnell JM (2019) Innate immune responses to paraquat exposure in a Drosophila model of Parkinson’s disease. Sci Rep 9:12714. https://doi.org/10.1038/s41598-019-48977-6
Mancuso R, del Valle J, Modol L et al (2014) Resveratrol improves motoneuron function and extends survival in SOD1G93A ALS mice. Neurotherapeutics. https://doi.org/10.1007/s13311-013-0253-y
McGuinness LA, Higgins JPT (2021) Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods 12:55–61. https://doi.org/10.1002/jrsm.1411
Meder D, Herz DM, Rowe JB et al (2019) The role of dopamine in the brain - lessons learned from Parkinson’s disease. Neuroimage 190:79–93. https://doi.org/10.1016/j.neuroimage.2018.11.021
Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741. https://doi.org/10.1016/j.cell.2011.10.026
Musgrove RE, Helwig M, Bae E-J et al (2019) Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer. J Clin Invest 129:3738–3753. https://doi.org/10.1172/JCI127330
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. https://doi.org/10.1126/science.1110647
Okawara M, Katsuki H, Kurimoto E et al (2007) Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. Biochem Pharmacol 73:550–560. https://doi.org/10.1016/j.bcp.2006.11.003
Palle S, Neerati P (2018) Improved neuroprotective effect of resveratrol nanoparticles as evinced by abrogation of rotenone-induced behavioral deficits and oxidative and mitochondrial dysfunctions in rat model of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol 391:445–453. https://doi.org/10.1007/s00210-018-1474-8
Panicker N, Sarkar S, Harischandra DS et al (2019) Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J Exp Med 216:1411–1430. https://doi.org/10.1084/jem.20182191
Parashar V, Rogina B (2009) dSir2 mediates the increased spontaneous physical activity in flies on calorie restriction. Aging (Albany NY) 1:529–541. https://doi.org/10.18632/aging.100061
Parker WD, Parks JK, Swerdlow RH (2008) Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res 1189:215–218. https://doi.org/10.1016/j.brainres.2007.10.061
Patel KR, Andreadi C, Britton RG et al (2013) Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3005870
Pathania A, Garg P, Sandhir R (2021) Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson’s disease: comparison of mice strains and dose regimens. Metab Brain Dis 36:2343–2357. https://doi.org/10.1007/s11011-021-00840-2
Peng K, Tao Y, Zhang J et al (2016) Resveratrol regulates mitochondrial biogenesis and fission/fusion to attenuate rotenone-induced neurotoxicity. Oxid Med Cell Longev 2016:1–12. https://doi.org/10.1155/2016/6705621
Perier C, Bové J, Vila M (2012) Mitochondria and programmed cell death in Parkinson’s disease: apoptosis and beyond. Antioxid Redox Signal 16:883–895. https://doi.org/10.1089/ars.2011.4074
Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009332–a009332. https://doi.org/10.1101/cshperspect.a009332
Pizzinat N, Copin N, Vindis C et al (1999) Reactive oxygen species production by monoamine oxidases in intact cells. Naunyn Schmiedebergs Arch Pharmacol 359:428–431. https://doi.org/10.1007/PL00005371
Poewe W, Seppi K, Tanner CM et al (2017) Parkinson disease. Nat Rev Dis Prim 3:17013. https://doi.org/10.1038/nrdp.2017.13
Pott Godoy MC, Tarelli R, Ferrari CC et al (2008) Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson’s disease. Brain 131:1880–1894. https://doi.org/10.1093/brain/awn101
Puspita L, Chung SY, Shim J (2017) Oxidative stress and cellular pathologies in Parkinson’s disease. Mol Brain 10:53. https://doi.org/10.1186/s13041-017-0340-9
Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353:777–783. https://doi.org/10.1126/science.aag2590
Rasheed MSU, Tripathi MK, Patel DK, Singh MP (2020) Resveratrol regulates Nrf2-mediated expression of antioxidant and xenobiotic metabolizing enzymes in pesticides-induced parkinsonism. Protein Pept Lett 27:1038–1045. https://doi.org/10.2174/0929866527666200403110036
Regitz C, Fitzenberger E, Mahn FL et al (2016) Resveratrol reduces amyloid-beta (Aβ1–42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans. Eur J Nutr 55:741–747. https://doi.org/10.1007/s00394-015-0894-1
Ribeiro De Lima MT, Waffo-Téguo P, Teissedre PL et al (1999) Determination of stilbenes (trans-astringin, cis- and trans-piceid, and cis- and trans-resveratrol) in Portuguese wines. J Agric Food Chem. https://doi.org/10.1021/jf9900884
Rizvi SI, Pandey KB (2010) Activation of the erythrocyte plasma membrane redox system by resveratrol: a possible mechanism for antioxidant properties. Pharmacol Reports 62:726–732. https://doi.org/10.1016/S1734-1140(10)70330-3
Romuk E, Szczurek W, Oleś M et al (2017) The evaluation of the changes in enzymatic antioxidant reserves and lipid peroxidation in chosen parts of the brain in an animal model of Parkinson disease. Adv Clin Exp Med 26:953–959. https://doi.org/10.17219/acem/63999
Rubinsztein DC, Codogno P, Levine B (2012) Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 11:709–730. https://doi.org/10.1038/nrd3802
Rubinsztein DC, Mariño G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695. https://doi.org/10.1016/j.cell.2011.07.030
Ryan SD, Dolatabadi N, Chan SF et al (2013) Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 155:1351–1364. https://doi.org/10.1016/j.cell.2013.11.009
Sadi G, Bozan D, Yildiz HB (2014) Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver. Mol Cell Biochem. https://doi.org/10.1007/s11010-014-2051-1
Satpute R, Pawar P, Puttewar S et al (2017) Effect of resveratrol and tetracycline on the subacute paraquat toxicity in mice. Hum Exp Toxicol 36:1303–1314. https://doi.org/10.1177/0960327116688070
Shimoji M, Pagan F, Healton EB, Mocchetti I (2009) CXCR4 and CXCL12 expression is increased in the nigro-striatal system of Parkinson’s disease. Neurotox Res 16:318–328. https://doi.org/10.1007/s12640-009-9076-3
Singh AK, Vinayak M (2017) Resveratrol alleviates inflammatory hyperalgesia by modulation of reactive oxygen species (ROS), antioxidant enzymes and ERK activation. Inflamm Res 66:911–921. https://doi.org/10.1007/s00011-017-1072-0
Singh SS, Rai SN, Birla H et al (2020) NF-κB-mediated neuroinflammation in Parkinson’s disease and potential therapeutic effect of polyphenols. Neurotox Res 37:491–507. https://doi.org/10.1007/s12640-019-00147-2
Sochocka M, Diniz BS, Leszek J (2017) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54:8071–8089. https://doi.org/10.1007/s12035-016-0297-1
Soo E, Thakur S, Qu Z et al (2016) Enhancing delivery and cytotoxicity of resveratrol through a dual nanoencapsulation approach. J Colloid Interface Sci 462:368–374. https://doi.org/10.1016/j.jcis.2015.10.022
Srivastava G, Dixit A, Yadav S et al (2012) Resveratrol potentiates cytochrome P450 2d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse. Free Radic Biol Med 52:1294–1306. https://doi.org/10.1016/j.freeradbiomed.2012.02.005
Sun Y, Sukumaran P, Selvaraj S et al (2018) TRPM2 promotes neurotoxin MPP+/MPTP-induced cell death. Mol Neurobiol 55:409–420. https://doi.org/10.1007/s12035-016-0338-9
Sur M, Dey P, Sarkar A et al (2018) Sarm1 induction and accompanying inflammatory response mediates age-dependent susceptibility to rotenone-induced neurotoxicity. Cell Death Discov 4:114. https://doi.org/10.1038/s41420-018-0119-5
Tangchirakhaphan S, Innajak S, Nilwarangkoon S et al (2018) Mechanism of apoptosis induction associated with ERK1/2 upregulation via goniothalamin in melanoma cells. Exp Ther Med. https://doi.org/10.3892/etm.2018.5762
Tokuşoǧlu Ö, Ünal MK, Yemiş F (2005) Determination of the phytoalexin resveratrol (3,5,4′-Trihydroxystilbene) in peanuts and pistachios by High-Performance Liquid Chromatographic Diode Array (HPLC-DAD) and Gas Chromatography-Mass Spectrometry (GC-MS). J Agric Food Chem. https://doi.org/10.1021/jf050496+
Torregrosa-Muñumer R, Vara E, Fernández-Tresguerres JÁ, Gredilla R (2021) Resveratrol supplementation at old age reverts changes associated with aging in inflammatory, oxidative and apoptotic markers in rat heart. Eur J Nutr 60:2683–2693. https://doi.org/10.1007/s00394-020-02457-0
Tran TN, Vo TNN, Frei K, Truong DD (2018) Levodopa-induced dyskinesia: clinical features, incidence, and risk factors. J Neural Transm 125:1109–1117. https://doi.org/10.1007/s00702-018-1900-6
Turk V, Stoka V, Vasiljeva O et al (2012) Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta - Proteins Proteomics 1824:68–88. https://doi.org/10.1016/j.bbapap.2011.10.002
Turner RS, Thomas RG, Craft S et al (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85:1383–1391. https://doi.org/10.1212/WNL.0000000000002035
Vallée A, Lecarpentier Y, Guillevin R, Vallée JN (2020) Circadian rhythms, Neuroinflammation and Oxidative Stress in the Story of Parkinson’s Disease. Cells 9:1–15. https://doi.org/10.3390/cells9020314
Vivekanantham S, Shah S, Dewji R et al (2015) Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int J Neurosci 125:717–725. https://doi.org/10.3109/00207454.2014.982795
Wang H, Dong X, Liu Z et al (2018a) Resveratrol suppresses rotenone-induced neurotoxicity through activation of SIRT1/Akt1 signaling pathway. Anat Rec 301:1115–1125. https://doi.org/10.1002/ar.23781
Wang L, Xu M, Liu C et al (2013) Resveratrols in grape berry skins and leaves in vitis germplasm. PLoS One 8:e61642. https://doi.org/10.1371/journal.pone.0061642
Wang XH, Souders CL, Zhao YH, Martyniuk CJ (2018b) Paraquat affects mitochondrial bioenergetics, dopamine system expression, and locomotor activity in zebrafish (Danio rerio). Chemosphere. https://doi.org/10.1016/j.chemosphere.2017.10.032
Wang Y, Lv D, Liu W et al (2018c) Disruption of the circadian clock alters antioxidative defense via the SIRT1-BMAL1 pathway in 6-OHDA-induced models of Parkinson’s disease. Oxid Med Cell Longev 2018:1–11. https://doi.org/10.1155/2018/4854732
Wang Y, Xu H, Fu Q et al (2011) Protective effect of resveratrol derived from Polygonum cuspidatum and its liposomal form on nigral cells in Parkinsonian rats. J Neurol Sci 304:29–34. https://doi.org/10.1016/j.jns.2011.02.025
Wang Z-H, Zhang J-L, Duan Y-L et al (2015) MicroRNA-214 participates in the neuroprotective effect of Resveratrol via inhibiting α-synuclein expression in MPTP-induced Parkinson’s disease mouse. Biomed Pharmacother 74:252–256. https://doi.org/10.1016/j.biopha.2015.08.025
Wu P-F, Xie N, Zhang J-J et al (2013) Resveratrol preconditioning increases methionine sulfoxide reductases A expression and enhances resistance of human neuroblastoma cells to neurotoxins. J Nutr Biochem 24:1070–1077. https://doi.org/10.1016/j.jnutbio.2012.08.005
Wu Y, Li X, Zhu JX et al (2011) Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neurosignals 19:163–174. https://doi.org/10.1159/000328516
Wu Z, Wu A, Dong J et al (2018) Grape skin extract improves muscle function and extends lifespan of a Drosophila model of Parkinson’s disease through activation of mitophagy. Exp Gerontol 113:10–17. https://doi.org/10.1016/j.exger.2018.09.014
Xia D, Sui R, Zhang Z (2019) Administration of resveratrol improved Parkinson’s disease-like phenotype by suppressing apoptosis of neurons via modulating the MALAT1/miR-129/SNCA signaling pathway. J Cell Biochem 120:4942–4951. https://doi.org/10.1002/jcb.27769
Yan W-J, Liu R-B, Wang L-K et al (2018) Sirt3-mediated autophagy contributes to resveratrol-induced protection against ER stress in HT22 cells. Front Neurosci. https://doi.org/10.3389/fnins.2018.00116
Yang L, Wang H, Liu L, Xie A (2018) The role of insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson’s disease dementia. Front Neurosci. https://doi.org/10.3389/fnins.2018.00073
Yu H-P, Hwang T-L, Hwang T-L et al (2010) Resveratrol prevents endothelial dysfunction and aortic superoxide production after trauma hemorrhage through estrogen receptor-dependent hemeoxygenase-1 pathway. Crit Care Med 38:1147–1154. https://doi.org/10.1097/CCM.0b013e3181cd124e
Yuan G, Hua B, Cai T et al (2017) Clock mediates liver senescence by controlling ER stress. Aging (Albany NY) 9:2647–2665. https://doi.org/10.18632/aging.101353
Yuan L, Zhou M, Huang D et al (2019) Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial- mesenchymal transition via the AKT/GSK-3β/Snail signaling pathway. Mol Med Rep. https://doi.org/10.3892/mmr.2019.10528
Yun SP, Kam T-I, Panicker N et al (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24:931–938. https://doi.org/10.1038/s41591-018-0051-5
Zeng W, Zhang W, Lu F et al (2017) Resveratrol attenuates MPP+-induced mitochondrial dysfunction and cell apoptosis via AKT/GSK-3β pathway in SN4741 cells. Neurosci Lett 637:50–56. https://doi.org/10.1016/j.neulet.2016.11.054
Zeng X, Zhang Y, Kwong JSW et al (2015) The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med 8:2–10. https://doi.org/10.1111/jebm.12141
Zhang J, Fan W, Wang H et al (2015) Resveratrol protects PC12 cell against 6-OHDA damage via CXCR4 signaling pathway. Evid Based Complement Alternat MEd 2015:1–12. https://doi.org/10.1155/2015/730121
Zhang L, Chen J, Yan L et al (2021) Resveratrol ameliorates cardiac remodeling in a murine model of heart failure with preserved ejection fraction. Front Pharmacol. https://doi.org/10.3389/fphar.2021.646240
Zhang L, Yu X, Ji M et al (2018) Resveratrol alleviates motor and cognitive deficits and neuropathology in the A53T α-synuclein mouse model of Parkinson’s disease. Food Funct 9:6414–6426. https://doi.org/10.1039/C8FO00964C
Zhang M, An C, Gao Y et al (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47. https://doi.org/10.1016/j.pneurobio.2012.09.003
Zhao J (2007) Interplay among nitric oxide and reactive oxygen species. Plant Signal Behav 2:544–547. https://doi.org/10.4161/psb.2.6.4802
Zhu Y, Wang B, Tao K et al (2017) Iron accumulation and microglia activation contribute to substantia nigra hyperechogenicity in the 6-OHDA-induced rat model of Parkinson’s disease. Parkinsonism Relat Disord 36:76–82. https://doi.org/10.1016/j.parkreldis.2017.01.003
Zou X-D, Guo S-Q, Hu Z-W, Li W-L (2016) NAMPT protects against 6-hydroxydopamine-induced neurotoxicity in PC12 cells through modulating SIRT1 activity. Mol Med Rep 13:4058–4064. https://doi.org/10.3892/mmr.2016.5034
Funding
This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) [Finance Code 001] and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [research grant 423028/2018–9].
Author information
Authors and Affiliations
Contributions
M.G. Santos and L. E. Schimith performed the search, selected the articles, and extracted data. M.A. Hort acted as the third reviewer in case of disagreements and checked all extracted information. All authors participated in the writing and reviewed the final version of the manuscript.
Corresponding author
Ethics declarations
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
dos Santos, M.G., Schimith, L.E., André-Miral, C. et al. Neuroprotective Effects of Resveratrol in In vivo and In vitro Experimental Models of Parkinson’s Disease: a Systematic Review. Neurotox Res 40, 319–345 (2022). https://doi.org/10.1007/s12640-021-00450-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-021-00450-x