Resveratrol upregulates brain-derived neurotrophic factor (BDNF) levels in reserpine-induced mice: A mechanistic extension study
DOI:
https://doi.org/10.65221/0229Keywords:
Resveratrol, reserpine, brain-derived neurotrophic factor (BDNF), hippocampus, neurotrophic hypothesis, depressionAbstract
Multiple research reports have shown that resveratrol exerts antidepressant-like effects through upregulation of brain-derived neurotrophic factor (BDNF) in various depression models. However, the operation of this mechanism in the classic reserpine-induced model, which depletes monoamines via inhibition of the vesicular monoamine transporter, remains poorly understood. Twenty-five mice served as subjects: The control group (group I, n=5) was treated orally with mormal saline (0.9% W/V). The remaining 20 mice were injected intraperitoneally with reserpine (0.2 mg/kg/day) for 16 days to induce depressive-like symptoms. Afterward, they were randomly divided into 4 groups (groups II-V, n=5). They were treated every other day with intraperitoneal injections of 0.2 mg/kg reserpine and once daily with 20 mg/kg fluoxetine, along with graded doses of resveratrol (30 mg/kg, 60 mg/kg). The treatment regimen lasted 15 days. Reserpine significantly (p < 0.05) reduced whole-brain BDNF levels and this reduction was significantly attenuated by resveratrol 60 mg/kg (p < 0.05) compared with the reserpine group alone. This study provides evidence that resveratrol at a higher dose upregulates BDNF in the reserpine model, thereby extending the neurotrophic mechanism to this classic monoamine-depletion paradigm.
References
Alwindi M, Bizanti A (2023). Vesicular monoamine transporter (VMAT) regional expression and roles in pathological conditions. Heliyon. Available at https://doi.org/10.1016/j.heliyon.2023.e22413
Antkiewicz-Michaluk L, Wasik A, Mozdzen E, Romanska I, Michaluk, J (2014). Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: Behavioural and neurochemical studies in the rat. Neurotoxicity Research 26:85-98.
Arosio B, Guerini FR, Voshaar RCO, Aprahamian I (2021). Blood brain-derived neurotrophic factor (BDNF) and depression. Do we have a translational perspective? Frontier in Behavioral Neuroscience. doi:10.3389/fnbeh.2021.626906
Basta M, Saleh SR, Aly RG, Dief AE (2023). Resveratrol ameliorates the behavioural and molecular changes in rats exposed to uninephrectomy: role of hippocampal SIRTi, BDNF and AchE. Journal of Physiology and Biochemistry 79:273-285.
Chen J, Shen J, Yu Z, Pan C, Han F, Zhu X, Xu H, Xu R, Wei T, Lu Y (2021). Accompanied by the attenuation of Dendrite/dendritic spine loss and the upregulation of BDNF/P-cofilin 1 levels in chronic restraint mice. Neurochemical Research 46:660-674.
Cubillos S, Engmann O, Brancato A (2022). BDNF as mediator of antidepressant response. Recent Advances and lifestyle interactions. International Journal of Molecular Sciences. Available at https://doi.org/10.3390/ijms232214445
Colucci-D’Amato L, Speranza, L, Volpicelli, F (2020). Neurotrophic Factor BDNF, Physiological functions and therapeutic potential in depression, neurodegeneration and cancer. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms21207777
Crawford CA, Williams MK, Shell AL, MacDonald KL, Considine RV, Wu W, Rand KL, Stewart JC (2023). Effects of modernized collaborative care for depression on brain-derived neurotrophic factor (BDNF) and depressive symptom clusters: Data from the elmpact trials. Psychiatry Research. Available at https://doi.org/10.106?psychres.2023.115581
Fahmy HM, Mohamed ER, Hussein AA, Khadrawy YA, Ahmed NA (2022). Evaluation of the therapeutic effect of mesoporous silica nanoparticles loaded with Gallic acid on reserpine-induced depression in Wistar rats. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-022-00579-1
Fine-Shamir N, Dahan A (2024). Solubility-enabling formulations for oral delivery of lipophilic drugs: considering the solubility-permeability interplay for accelerated formulation development. Expert Opinion on Drug Delivery 21(1):13-29.
Fiore M, Terracina S, Ferraguti G (2025). Brain Neurotrophins and Plant Polyphenols: A Powerful Connection. Molecules. https://doi.org/10.3390/molecules30122657.
Ge L, Liu L, Liu H, Liu S, Xue H, Wang X, Yuan L, Wang X, Yuan L, Wang Z, Liu D (2015). Resveratrol abrogates lipopolysaccharide-induced depressive-like behaviour, neuroinflammatory response and CREB/BDNF signaling in mice. European Journal of Pharmacology 768:49-57.
Govindarajulu M, Shanker T, Patel S, Fabbrini M, Amulja M, Ramesh S, Bovvalingaiah P, Sharma S, Clark RC, Deruiter J, Moore T, Agrawal, DS, Dhanasekaran, M (2021). Reserpine-induced depression and other neurotoxicity: A monoaminergic hypothesis. Medicinal Herbs and Fungi, Springer Singapore, pp 293-313.
Hiu X, Zhang Z, Chen G, Ge M, Yu Z, Shen J, Ran C, Han F, Zhu X, Lu Y (2025). Resveratrol improves ovariectomy and chronic restraint stress-induced depression-like behaviours in mice through brain-derived neurotrophic factor associated structural synaptical remodelling. Behavioural Pharmacology 36(6):344-377.
Jie S, Fu A, Wang C, Rajabi S (2025). A comprehensive review on the impact of polyphenol supplementation and exercise on depression and brain function parameters. Behavioural and Brain functions. https://doi.org/10.1186/s12993-025-00273-2
Khadrawy YA, Sawie HG, Hosny EN, Mourad HH (2018). Assessment of the antidepressant effect of caffeine using rat model of depression induced by reserpine. Bulletin of the National Research Centre 42:36.
Kharazmi M, Khalili T, Dehghan-Shasaltaneh M, Bahari A, Ebrahimi-Ghiri M (2026). Resveratrol prevents arsenic-induced depression-like phenotypes via modulation of BDNF signaling. Behavioural Brain Research. Available at https://doi.org/10.1016/j.bbr.2025.115988
Kramer M, Front E (2017). Reducing sample size in experiment with animals: historical controls and related strategies. Biological Reviews 92:431-445.
Kristiyani A, Ikawati 0Z, Gani, AP, Sofro ZM (2025). Animal models for antidepressant activity assay on natural and conventional agents: A review of preclinical testing. Journal of Herbmed Pharmacology 13(4):523-536.
Kuzay D, Dilekoz E, Ozer C (2022). Effects of thymoquinone in a rat model of reserpine- induced depression. Brazilian Journal of Pharmaceutical Sciences http://dx.doi.org/10.1390/s2175-979022e19847
Lazarova M, Stefanova M, Tsvetanova E, Georgieva A, Tashaeva K, Radeva L, Yoncheva K (2024). Resveratrol-loaded pluronic micelles ameliorate scopolamine-induced cognitive dysfunction targeting acetylcholinesterase activity and programmed cell death. International Journal of Molecular Sciences. https: //doi.org/10.3390/ijms252312777
Lis A, Maj P, Swietek A, Romuk E (2025). The role of various types of diets in the treatment of depressive disorders. Medicina. https://doi.org/10.3390/medicina61101737
Liu L, Zhang Q, Cai Y, Sun D, He X, Wang L, Yu D, Li X, Xiang X, Xu H, Yang Q, Fan X (2016). Resveratrol counteracts lipopolysaccharide-induced depressive-like behavior via enhanced hippocampal neurogenesis. Oncotarget 7:56045- 56059.
Moore A, Beidler J, Hong MY (2018). Resveratrol and Depression in animal models: A systematic review of the biological mechanisms. Molecules 23(9):2197.
Numakawa T, Kajihara R (2025). The role of Brain-derived neurotropic factor as an essential mediator in neuronal functions and the therapeutic potential of its mimetics for neuroprotection in neurologic and psychiatric disorders. Molecules. doi: 10.3390/molecules30040848
Shen, J, Qu C, Xu L, Sun H, Zhang J (2019). Resveratrol exerts a protective effect in chronic unpredictable mild stress-induced depressive -like behaviour: involvement of the AKT/GSK3 signalling pathway in hippocampus. Psychopharmacology 236:591-602.
Strawbridge R, Javed RR, Cave J, Jauhar S, Yong AH (2023). The effects of reserpine on depression: A systematic review. Journal of Psychopharmacology 37(3):248-260.
Toader C, Serbian M, Munteanu O, Covache-Busuioc R, Enyedi M, Ciurea, AV, Tatanu, CP (2025). From synaptic Plasticity to neurodegeneration: BDNF as a transformative target in Medicine. International Journal of Molecular Sciences. Available at https://doi.org/10.3390/ijms26094271
Varghese TP, Singh R, Chand S (2025). The role of brain-derived neurotrophic factor (BDNF) in depression: a narrative review. The Open Biomarkers of Journal. Available at doi: 10.2174/0118753183381834250617133639
Wang, Z, Gu, J, Wang, X, Xie, K, Luan, Q, Wan, N, Zhang, Q, Jiang, H, Liu, D (2013). Antidepressant-like activity of resveratrol treatment in the forced swim test and tail suspension test in mice: the HPA axis, BDNF expression and Phosphorylation of ERK. Pharmacology Biochemistry and Behavior 112:104-110.
Wu Y, Zhu Y, Zhang S, Mingxing D (2025). Resveratrol alleviates depression-like behaviour via the activation of SIRT1/NF-KB signaling pathway in microglia. Future Science. Available at doi: 10:1080/20565623.2025.2463852
Xu N, He Y, Wei Y, Bai L, Wang L (2025). Possible antidepressant mechanism of acupuncture: targeting neuroplasticity. Frontiers in Neurosciences. doi: 10.3389/fnins.2025.1512073
Yang X, Song S, Xu Y (2017). Resveratrol ameliorates chronic unpredictable mild stress-induced depression-like behaviour: involvement of the HPA axis, inflammatory markers, BDNF and Wnt/β – catenin pathway in rats. Neuropsychiatric Disease and Treatment 13: 2727-2736.
Zhang F, Lu YF, Wu Q, Liu J, Shi JS (2012). Resveratrol promoters neurotropic factor release from Astroglia. Experimental Biology and Medicine 8:943-948.
Zhang Q, Wang X, Bai X, Xie Y, Zhang T, Bo S, Chen X (2017). Resveratrol reversed chronic restraint stress-induced impaired cognitive function in rats. Molecular medicine reports 16:2095-2100.
Zhao R, Master B.Q, Master BM, Gi Y (2019). Improving activity of Lyciumbarbarum polysaccharide on depressive mice induced by reserpine. Iranian Journal of Pharmaceutical Research 18(3):1556-1565.
