Resveratrol exerts a protective effect in chronic unpredictable mild stress–induced depressive-like behavior: involvement of the AKT/GSK3β signaling pathway in hippocampus
- 204 Downloads
Chronic unpredictable mild stress (CUMS) is an important contributing factor for depression with inflammatory response alteration, neuron apoptosis, and decreased neurogenesis. Previous study reported that the administration of resveratrol alleviated depression by normalizing the increased proinflammatory cytokine levels and inhibiting apoptosis in the hippocampus. However, the upstream signaling pathway that regulates cytokines and apoptosis in the antidepressant effect of resveratrol remains unclear.
The objective of this study is to investigate the possible mechanism of the effect of resveratrol on depression.
Male Sprague Dawley rats were exposed to CUMS for four consecutive weeks to elicit depressive-like behavior. The rats in the drug treatment groups were injected with resveratrol (40 or 80 mg/kg/day) and fluoxetine (10 mg/kg/day) intraperitoneally for 4 weeks. Rats in two additional groups were administered LY294002 by bilateral stereotaxic microinjection into the lateral ventricle before resveratrol administration. Behavioral tests, including sucrose preference test, forced swim test, and open field test, were used after 4 weeks of a CUMS procedure to appraise depressive-like behavior. Then, the proinflammatory cytokines (TNF-α, IL-6, and IL-1β) in the hippocampus and prefrontal cortex (PFC) tissues of rats were measured. Apoptosis-related molecules such as Bax and Bcl-2 mRNA levels in the hippocampus were analyzed. Furthermore, p-Akt/Akt and p-GSK3β/GSK3β protein expression in the hippocampus were also measured.
The results show that rats were subjected to CUMS procedure exhibited depressive-like behavior, increased TNF-α, IL-6, and IL-1β levels in hippocampus and PFC, alteration of Bax and Bcl-2 mRNA levels in hippocampus, decreased p-Akt/Akt and p-GSK3β/GSK3β protein expression in hippocampus, and an increased apoptotic cell percentage in the hippocampal CA1 region. However, resveratrol (40 or 80 mg/kg) treatment reversed these behavioral and molecular changes in CUMS rats. The positive control drug fluoxetine showed a similar effect as the resveratrol treatment. When rats were injected with LY294002 before resveratrol treatment, the antidepressant effect of resveratrol was significantly attenuated, TNF-α, IL-6 and IL-1β levels in hippocampus and PFC increased again, Bax mRNA levels increased and Bcl-2 mRNA levels decreased in hippocampus, and Akt/GSK3β protein expression in hippocampus decreased.
The findings in the present study suggest that the antidepressant effect of resveratrol treatment may act through activation of the Akt/GSK3β signaling pathway and then regulation of proinflammatory cytokine expression and alteration of apoptosis.
KeywordsChronic unpredictable mild stress Resveratrol Proinflammatory cytokines Apoptosis
The study was financially supported by the National Natural Science Foundation of China (No.81371196).
Compliance with ethical standards
All experiments were performed according to the NIH guidelines and approved by the Animal Ethics Committee of the Medical Department of Wuhan University.
Conflict of interest
The authors declare that they have no conflict of interest.
- Akpinar A, Uğuz AC, Nazıroğlu M (2014) Agomelatine and duloxetine synergistically modulates apoptotic pathway by inhibiting oxidative stress triggered intracellular calcium entry in neuronal PC12 cells: role of TRPM2 and voltage-gated calcium channels. J Membr Biol 247: 451–9Google Scholar
- Ali SH, Madhana RM, K V A, Kasala ER, Bodduluru LN, Pitta S, Mahareddy JR, Lahkar M (2015) Resveratrol ameliorates depressive-like behavior in repeated corticosterone-induced depression in mice. Steroids 101: 37–42Google Scholar
- Kara A, Unal D, Simsek N, Yucel A, Yucel N, Selli J (2014) Ultra-structural changes and apoptotic activity in cerebellum of post-menopausal-diabetic rats: a histochemical and ultra-structural study. Gynecol Endocrinol 30: 226–31Google Scholar
- Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS (2009) Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp 30: 3719–35Google Scholar
- MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C, Young LT (2003) Course of illness hippocampal function, and hippocampal volume in major depression. Peoc Natl Acad Sci USA 100: 1387–92Google Scholar
- Morais M, Santos PA, Mateus-Pinheiro A, Patricio P, Pinto L, Sousa N, Pedroso P, Almeida S, Filipe A, Bessa JM (2014) The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition. J Psychopharmacol 28:1178–1183CrossRefGoogle Scholar
- Pan B, Liu Y (2015) Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression. Int J Clin Exp Pathol 8:15454–15461Google Scholar
- Savitz J, Drevets WC, Smith CM, Victor TA, Wurfel BE, Bellgowan PS, Bodurka J, Teague TK, Dantzer R (2015) Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology 40: 463–71Google Scholar
- Shen J, Zhang J, Deng M, Liu Y, Hu Y, Zhang L (2016) The antidepressant effect of Angelica sinensis extracts on chronic unpredictable mild stress-induced depression is mediated via the upregulation of the BDNF signaling pathway in rats. Evid Based Complement Alternat Med 2016:7434692Google Scholar
- Turenne GA, Price BD (2001) Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53׳s transcriptional activity. BMC Cell Biol 2:12Google Scholar
- Wang X, Xie Y, Zhang T, Bo S, Bai X, Liu H, Li T, Liu S, Zhou Y, Cong X, Wang Z, Liu D (2016) Resveratrol reverses chronic restraint stress-induced depression-like behaviour: involvement of BDNF level, ERK phosphorylation and expression of Bcl-2 and Bax in rats. Brain Res Bull 125:134–143CrossRefGoogle Scholar
- Wang Y, Kuramitsu Y, Baron B, Kitagawa T, Tokuda K, Akada J, Maehara SI, Maehara Y, Nakamura K (2017) PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. Int J Oncol 50: 606–612Google Scholar
- Yazir Y, Utkan T, Aricioglu F (2012) Inhibition of neuronal nitric oxide synthase and soluble guanylate cyclase prevents depression-like behaviour in rats exposed to chronic unpredictable mild stress. Basic Clin Pharmacol Toxicol 111:154–160Google Scholar