Resveratrol’s potential in the prevention and treatment of neurodegenerative diseases: molecular mechanisms

Abstract

The increasing prevalence of neurodegenerative diseases (NDs), such as Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis, and amyotrophic lateral sclerosis, represents a serious global public health issue. Consequently, the search for compounds with neuroprotective potential has intensified. In this context, resveratrol (RSV), a stilbene polyphenol found mainly in red grapes, exhibits important pharmacological properties, such as antioxidant and anti-inflammatory, and has been widely investigated in neuroscience due to its potential in the prevention and treatment of NDs. This narrative review was conducted using the PubMed^® database, with the keywords “resveratrol”, “molecular mechanisms”, “mechanisms of action”, “neuroinflammation”, “oxidative stress”, “autophagy”, “gene regulation”, and “clinical studies”. This study discusses the molecular mechanisms of RSV on NDs, focusing on signaling pathways involved in neuroinflammation, oxidative stress, gene regulation, autophagy, and cell death. Intracellular pathways such as NF-κB, JAK/STAT, MAPK/ERK, PI3K/Akt, and Nrf2/Keap1 are associated with immune modulation mediated by RSV, leading to a decrease in oxidative stress, induction of autophagy, and inhibition of apoptosis. RSV has pharmacokinetic limitations, such as low bioavailability and stability, although RSV can cross the blood-brain barrier. Thus, researches involving nonencapsulated formulations aim to enhance their delivery to the central nervous system. Current in vitro and in vivo studies are promising, although further clinical trials are needed, as few have been conducted and available data remain preliminary. In conclusion, RSV presents multiple benefits to neurological health and shows therapeutic potential in NDs; however, additional clinical studies and translational research are essential to validate and optimize its application.

Keywords

neurodegenerative disorders / neuroprotective agent / polyphenol / antioxidants / epigenetics

References

[1] Armstrong R. What causes neurodegenerative disease? Folia Neuropathol. 2020; 58: 93-112.

[2] Medina A, Mahjoub Y, Shaver L, Pringsheim T. Prevalence and Incidence of Huntington’s Disease: An Updated Systematic Review and Meta-Analysis. Mov Disord. 2022; 37: 2327-35.

[3] Zhu J, Cui Y, Zhang J, Yan R, Su D, Zhao D, et al. Temporal trends in the prevalence of Parkinson’s disease from 1980 to 2023: a systematic review and meta-analysis. Lancet Healthy Longev. 2024; 5: e464-79.

[4] Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech. 2017; 10: 499-502.

[5] Kritsilis M, V Rizou S, Koutsoudaki PN, Evangelou K, Gorgoulis VG, Papadopoulos D. Ageing, Cellular Senescence and Neurodegenerative Disease. Int J Mol Sci. 2018; 19: 2937.

[6] Tian B, Liu J. Resveratrol: a review of plant sources, synthesis, stability, modification and food application. J Sci Food Agric. 2020; 100: 1392-404.

[7] Jaa A, de Moura PHB, Valls-Fonayet J, Da Costa G, Ruiz-Larrea MB, Krisa S, et al. Stilbenes in Red Wine: Formation and Biological Potential of Resveratrol and Piceid Dimers. Molecules. 2024; 29: 6067.

[8] Silva P, Rodríguez-Pérez M, Gómez-Torres Ó, Burgos-Ramos E. Olive oil and wine as source of multi-target agents in the prevention of Alzheimer disease. Nutr Res Rev. 2023; 36: 140-54.

[9] Zhang Y, Yuan D, Guo J, Jiang J, Yao H, Chen Z, et al. Integrated LC-MS/MS method and network pharmacology for exploring the characterization and mechanism of neuroprotective effect of Vitis amurensis Rupr. wine polyphenol. J Food Biochem. 2022; 46: e14316.

[10] Zhang L, Li C, Kakar MU, Khan MS, Wu P, Amir RM, et al. Resveratrol (RV): A pharmacological review and call for further research. Biomed Pharmacother. 2021; 143: 112164.

[11] Müller L, Di Benedetto S. Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation. Front Cell Neurosci. 2025; 19: 1575022.

[12] Yoon CS. Natural Products in the Treatment of Neuroinflammation at Microglia: Recent Trend and Features. Cells. 2025; 14: 571.

[13] Chi H, Chang HY, Sang TK. Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases. Int J Mol Sci. 2018; 19: 3082.

[14] Tao G, Wang X, Wang J, Ye Y, Zhang M, Lang Y, et al. Dihydro-resveratrol ameliorates NLRP3 inflammasome-mediated neuroinflammation via Bnip3-dependent mitophagy in Alzheimer’s disease. Br J Pharmacol. 2025; 182: 1005-24.

[15] Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflammation. 2017; 14: 1.

[16] Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, et al. Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. J Neurochem. 2012; 120: 461-72.

[17] Yokoyama T, Suzuki R, Mizuguchi M. Crystal structure of death-associated protein kinase 1 in complex with the dietary compound resveratrol. IUCrJ. 2021; 8: 131-8.

[18] Zhao Y, Lin M, Zhai F, Chen J, Jin X. Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease. Pharmaceuticals (Basel). 2024; 17: 782.

[19] Qureshi AA, Guan XQ, Reis JC, Papasian CJ, Jabre S, Morrison DC, et al. Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids Health Dis. 2012; 11: 76.

[20] Livraghi V, Mazza L, Chiappori F, Cardano M, Cazzalini O, Puglisi R, et al. A proteasome-dependent inhibition of SIRT-1 by the resveratrol analogue 4,4’-dihydroxy- trans-stilbene. J Tradit Complement Med. 2024; 14: 534-43.

[21] Singh A, Yadawa AK, Chaturvedi S, Wahajuddin M, Mishra A, Singh S. Mechanism for antiParkinsonian effect of resveratrol: Involvement of transporters, synaptic proteins, dendrite arborization, biochemical alterations, ER stress and apoptosis. Food Chem Toxicol. 2021; 155: 112433.

[22] Vidoni C, Secomandi E, Castiglioni A, Melone MAB, Isidoro C. Resveratrol protects neuronal-like cells expressing mutant Huntingtin from dopamine toxicity by rescuing ATG4-mediated autophagosome formation. Neurochem Int. 2018; 117: 174-87.

[23] Yoon J, Ku D, Lee M, Lee N, Im SG, Kim Y. Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress. Int J Mol Sci. 2023; 24: 7403.

[24] Ho DJ, Calingasan NY, Wille E, Dumont M, Beal MF. Resveratrol protects against peripheral deficits in a mouse model of Huntington’s disease. Exp Neurol. 2010; 225: 74-84.

[25] Naia L, Rosenstock TR, Oliveira AM, Oliveira-Sousa SI, Caldeira GL, Carmo C, et al. Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models. Mol Neurobiol. 2017; 54: 5385-99.

[26] Rizea RE, Corlatescu AD, Costin HP, Dumitru A, Ciurea AV. Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances. Int J Mol Sci. 2024; 25: 9966.

[27] Han S, Choi J, Soon Shin K, Kang SJ. Resveratrol upregulated heat shock proteins and extended the survival of G93A-SOD1 mice. Brain Res. 2012; 1483: 112-7.

[28] Wang J, Zhang Y, Tang L, Zhang N, Fan D. Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis. Neurosci Lett. 2011; 503: 250-5.

[29] Yun YC, Jeong S, Kim SH, Cho GW. Reduced sirtuin 1/adenosine monophosphate-activated protein kinase in amyotrophic lateral sclerosis patient-derived mesenchymal stem cells can be restored by resveratrol. J Tissue Eng Regen Med. 2019; 13: 110-5.

[30] Parrella E, Porrini V, Scambi I, Gennari MM, Gussago C, Bankole O, et al. Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis. Front Pharmacol. 2022; 13: 1017364.

[31] Markert CD, Kim E, Gifondorwa DJ, Childers MK, Milligan CE. A single-dose resveratrol treatment in a mouse model of amyotrophic lateral sclerosis. J Med Food. 2010; 13: 1081-5.

[32] Cao D, Wang M, Qiu X, Liu D, Jiang H, Yang N, et al. Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol. Genes Dev. 2015; 29: 1316-25.

[33] Yu Y, Li S, Kong L, Du Y, Liu Y, Zang J, et al. Development of a brain-targeted nano drug delivery system to enhance the treatment of neurodegenerative effects of resveratrol. J Liposome Res. 2024; 34: 435-51.

[34] Pinheiro DML, de Oliveira AHS, Coutinho LG, Fontes FL, de Medeiros Oliveira RK, Oliveira TT, et al. Resveratrol decreases the expression of genes involved in inflammation through transcriptional regulation. Free Radic Biol Med. 2019; 130: 8-22.

[35] Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009; 1: a001651.

[36] Ma C, Wang Y, Dong L, Li M, Cai W. Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways. Acta Biochim Biophys Sin (Shanghai). 2015; 47: 207-13.

[37] Luo L, Wang F, Xu X, Ma M, Kuang G, Zhang Y, et al. STAT3 promotes NLRP3 inflammasome activation by mediating NLRP3 mitochondrial translocation. Exp Mol Med. 2024; 56: 1980-90.

[38] Zhang C, Peng Q, Tang Y, Wang C, Wang S, Yu D, et al. Resveratrol ameliorates glioblastoma inflammatory response by reducing NLRP3 inflammasome activation through inhibition of the JAK2/STAT3 pathway. J Cancer Res Clin Oncol. 2024; 150: 168.

[39] Alqahtani T, Deore SL, Kide AA, Shende BA, Sharma R, Dadarao Chakole R, et al. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis -An updated review. Mitochondrion. 2023; 71: 83-92.

[40] Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci. 2012; 322: 254-62.

[41] Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Lett. 2018; 592: 692-702.

[42] Kong Q, Lin CLG. Oxidative damage to RNA: mechanisms, consequences, and diseases. Cell Mol Life Sci. 2010; 67: 1817-29.

[43] Esmaeili Y, Yarjanli Z, Pakniya F, Bidram E, Łos MJ, Eshraghi M, et al. Targeting autophagy, oxidative stress, and ER stress for neurodegenerative disease treatment. J Control Release. 2022; 345: 147-75.

[44] Martin LJ. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases. Pharmaceuticals (Basel). 2010; 3: 839-915.

[45] Maritim AC, Sanders RA, Watkins JB 3rd. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003; 17: 24-38.

[46] Bekyarova GY, Vankova DG, Madjova VH, Bekyarov NA, Salim AS, Ivanova DG, et al. Association between Nfr2, HO-1, NF-κB Expression, Plasma ADMA, and Oxidative Stress in Metabolic Syndrome. Int J Mol Sci. 2023; 24: 17067.

[47] Saha S, Buttari B, Panieri E, Profumo E, Saso L. An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules. 2020; 25: 5474.

[48] Sivinski J, Zhang DD, Chapman E. Targeting NRF2 to treat cancer. Semin Cancer Biol. 2021; 76: 61-73.

[49] Wu L, Chen Q, Dong B, Han D, Zhu X, Liu H, et al. Resveratrol attenuated oxidative stress and inflammatory and mitochondrial dysfunction induced by acute ammonia exposure in gibel carp (Carassius gibelio). Ecotoxicol Environ Saf. 2023; 251: 114544.

[50] Chi F, Cheng C, Zhang M, Su B, Hou Y, Bai G. Resveratrol targeting NRF2 disrupts the binding between KEAP1 and NRF2-DLG motif to ameliorate oxidative stress damage in mice pulmonary infection. J Ethnopharmacol. 2024; 332: 118353.

[51] Kato K, Takahashi M, Oh-Hashi K, Ando K, Hirata Y. Quercetin and resveratrol inhibit ferroptosis independently of Nrf2-ARE activation in mouse hippocampal HT22 cells. Food Chem Toxicol. 2023; 172: 113586.

[52] Chiang MC, Nicol CJB, Lo SS, Hung SW, Wang CJ, Lin CH. Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture. Int J Mol Sci. 2022; 23: 11678.

[53] Xu X, Pang Y, Fan X. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduct Target Ther. 2025; 10: 190.

[54] Zeng W, Zhang W, Lu F, Gao L, Gao G. Resveratrol attenuates MPP⁺-induced mitochondrial dysfunction and cell apoptosis via AKT/GSK-3β pathway in SN4741 cells. Neurosci Lett. 2017; 637: 50-6.

[55] Force T, Woodgett JR. Unique and overlapping functions of GSK-3 isoforms in cell differentiation and proliferation and cardiovascular development. J Biol Chem. 2009; 284: 9643-7.

[56] Guha S, Cullen JP, Morrow D, Colombo A, Lally C, Walls D, et al. Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival. Basic Res Cardiol. 2011; 106: 773-85.

[57] Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS. Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem. 2003; 278: 48872-9.

[58] Feng S, Gui J, Qin B, Ye J, Zhao Q, Guo A, et al. Resveratrol Inhibits VDAC1-Mediated Mitochondrial Dysfunction to Mitigate Pathological Progression in Parkinson’s Disease Model. Mol Neurobiol. 2025; 62: 6636-54.

[59] Silveira IA, Mullis AS, Cairns DM, Shevzov-Zebrun A, Whalen J, Galuppo A, et al. Screening neuroprotective compounds in herpes-induced Alzheimer’s disease cell and 3D tissue models. Free Radic Biol Med. 2022; 186: 76-92.

[60] Sawda C, Moussa C, Turner RS. Resveratrol for Alzheimer’s disease. Ann N Y Acad Sci. 2017; 1403: 142-9.

[61] Zemheri-Navruz F, Ince S, Arslan-Acaroz D, Acaroz U, Demirel HH, Demirkapi EN. Resveratrol alleviates pyraclostrobin-induced lipid peroxidation, oxidative stress, and DNA damage in rats. Environ Sci Pollut Res Int. 2023; 30: 6414-23.

[62] Ordaz DA, Gupta K, Bota DA. The role of Poly-ADP ribose polymerase (PARP) enzymes in chemotherapy-induced cognitive impairments - parallels with other neurodegenerative disorders. Front Pharmacol. 2025; 16: 1615843.

[63] Breunig K, Lei X, Montalbano M, Guardia GDA, Ostadrahimi S, Alers V, et al. SERBP1 interacts with PARP1 and is present in PARylation-dependent protein complexes regulating splicing, cell division, and ribosome biogenesis. Elife. 2025; 13: RP98152.

[64] Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005; 280: 17187-95.

[65] Palmer JE, Wilson N, Son SM, Obrocki P, Wrobel L, Rob M, et al. Autophagy, aging, and age-related neurodegeneration. Neuron. 2025; 113: 29-48.

[66] Li L, Li Q, Huang W, Han Y, Tan H, An M, et al. Dapagliflozin Alleviates Hepatic Steatosis by Restoring Autophagy via the AMPK-mTOR Pathway. Front Pharmacol. 2021; 12: 589273.

[67] Hu Y, Chen H, Zhang L, Lin X, Li X, Zhuang H, et al. The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy. 2021; 17: 1142-56.

[68] Wang G, Xie X, Yuan L, Qiu J, Duan W, Xu B, et al. Resveratrol ameliorates rheumatoid arthritis via activation of SIRT1-Nrf2 signaling pathway. Biofactors. 2020; 46: 441-53.

[69] Ungurianu A, Zanfirescu A, Margină D. Sirtuins, resveratrol and the intertwining cellular pathways connecting them. Ageing Res Rev. 2023; 88: 101936.

[70] Zhang J, Ping J, Jiang N, Xu L. Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways. J Food Biochem. 2022; 46: e14463.

[71] Baek SH, Ko JH, Lee H, Jung J, Kong M, Lee JW, et al. Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells. Phytomedicine. 2016; 23: 566-77.

[72] Baeken MW. Sirtuins and their influence on autophagy. J Cell Biochem. 2024; 125: e30377.

[73] Thapa R, Moglad E, Afzal M, Gupta G, Bhat AA, Hassan Almalki W, et al. The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective. Ageing Res Rev. 2024; 102: 102545.

[74] Li J, Liu T, Xian M, Wei J. Therapeutic applications of exercise in neurodegenerative diseases: focusing on the mechanism of SIRT1. Mol Cell Biochem. 2025; 480: 4921-39.

[75] Zhu L, Yang M, Fan L, Yan Q, Zhang L, Mu P, et al. Interaction between resveratrol and SIRT1: role in neurodegenerative diseases. Naunyn Schmiedebergs Arch Pharmacol. 2025; 398: 89-101.

[76] Wei L, Chai S, Yue C, Zhang H, Li J, Qin N. Resveratrol protects osteocytes against oxidative stress in ovariectomized rats through AMPK/JNK1-dependent pathway leading to promotion of autophagy and inhibition of apoptosis. Cell Death Discov. 2023; 9: 16.

[77] McManus RM, Latz E. NLRP3 inflammasome signalling in Alzheimer’s disease. Neuropharmacology. 2024; 252: 109941.

[78] Abadin X, de Dios C, Zubillaga M, Ivars E, Puigròs M, Marí M, et al. Neuroinflammation in Age-Related Neurodegenerative Diseases: Role of Mitochondrial Oxidative Stress. Antioxidants (Basel). 2024; 13: 1440.

[79] Wang Q, Yang S, Zhang X, Zhang S, Chen L, Wang W, et al. Inflammasomes in neurodegenerative diseases. Transl Neurodegener. 2024; 13: 65.

[80] Walker DG, Whetzel AM, Lue LF. Expression of suppressor of cytokine signaling genes in human elderly and Alzheimer’s disease brains and human microglia. Neuroscience. 2015; 302: 121-37.

[81] Porro C, Cianciulli A, Trotta T, Lofrumento DD, Panaro MA. Curcumin Regulates Anti-Inflammatory Responses by JAK/STAT/SOCS Signaling Pathway in BV-2 Microglial Cells. Biology (Basel). 2019; 8: 51.

[82] Pocock J, Vasilopoulou F, Svensson E, Cosker K. Microglia and TREM2. Neuropharmacology. 2024; 257: 110020.

[83] Hou Y, Wang K, Wan W, Cheng Y, Pu X, Ye X. Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats. Genes Dis. 2018; 5: 245-55.

[84] Aliyari M, Ghoflchi S, Hashemy SI, Hashemi SF, Reihani A, Hosseini H. The PI3K/Akt pathway: a target for curcumin’s therapeutic effects. J Diabetes Metab Disord. 2025; 24: 52.

[85] Jhanji M, Bhan A, Arrowood C, Yakout DW, Shroff A, McManus D, et al. Tyrosine and Phenylalanine Activate Neuronal DNA Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to TyrRS/YARS1 Depletion. IUBMB Life. 2025; 77: e70030.

[86] Utpal BK, Mokhfi FZ, Zehravi M, Sweilam SH, Gupta JK, Kareemulla S, et al. Resveratrol: A Natural Compound Targeting the PI3K/Akt/mTOR Pathway in Neurological Diseases. Mol Neurobiol. 2025; 62: 5579-608.

[87] Mancuso R, del Valle J, Modol L, Martinez A, Granado-Serrano AB, Ramirez-Núñez O, et al. Resveratrol improves motoneuron function and extends survival in SOD1(G93A) ALS mice. Neurotherapeutics. 2014; 11: 419-32.

[88] Rivadeneyra-Domínguez E, Zamora-Bello I, Juárez-Zaragoza ER, Rosales-Sánchez Ó, Guillén-Ruiz G, Rodríguez-Landa JF. Resveratrol reverses cassava (Manihot esculenta Crantz) juice-induced motor impairment in the Wistar rat. BMC Complement Med Ther. 2025; 25: 1-13.

[89] Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, et al. Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer’s disease. FASEB J. 2006; 20: 2313-20.

[90] Navarro G, Martínez-Pinilla E, Sánchez-Melgar A, Ortiz R, Noé V, Martín M, et al. A genomics approach identifies selective effects of trans-resveratrol in cerebral cortex neuron and glia gene expression. PLoS One. 2017; 12: e0176067.

[91] Sánchez-Melgar A, Izquierdo-Ramírez PJ, Griñán-Ferré C, Pallàs M, Martín M, Albasanz JL. Neuroprotective Effects of Resveratrol by Modifying Cholesterol Metabolism and Aβ Processing in SAMP8 Mice. Int J Mol Sci. 2022; 23: 7580.

[92] Sánchez-Melgar A, Albasanz JL, Palomera-Ávalos V, Pallàs M, Martín M. Resveratrol Modulates and Reverses the Age-Related Effect on Adenosine-Mediated Signalling in SAMP8 Mice. Mol Neurobiol. 2019; 56: 2881-95.