Resveratrol exerts anti-inflammatory and neuroprotective effects to prevent memory deficits in rats exposed to chronic unpredictable mild stress Yusufhan Yazir a , Tijen Utkan b,c, ⁎, Nejat Gacar b , Feyza Aricioglu d, ⁎ a Kocaeli University Faculty of Medicine, Department of Histology and Embryology, Kocaeli, Turkey b Kocaeli University Faculty of Medicine, Department of Pharmacology, Kocaeli, Turkey c Kocaeli University Experimental Medical Research and Application Centre, Kocaeli, Turkey d Marmara University Faculty of Pharmacy, Department of Pharmacology and Psychopharmacology Unit, Istanbul, Turkey HIGHLIGHTS • Resveratrol attenuates the deficits in cognition seen in stressed rats. • Resveratrol decreased proinflammatory cytokine concentrations in plasma. • Resveratrol improved neurothrophic factor expression in hippocampus and amygdala. • Resveratrol have a role in reversing the deleterious effects of stress on cognition. abstract article info Article history: Received 25 April 2014 Accepted 10 October 2014 Available online 22 October 2014 Keywords: Resveratrol Chronic mild stress learning Memory BDNF c-Fos TNF-α IL-1β A number of studies have recently focused on the neuroprotective and anti-inflammatory effects of resveratrol. In prior studies, we described its beneficial effects on scopolamine-induced learning deficits in rats. The aim of this study was to investigate the effects of resveratrol on emotional and spatial cognitive functions, neurotropic factor expression, and plasma levels of proinflammatory cytokines in rats exposed to chronic unpredictable mild stress (CUMS), which is known to induce cognitive deficits. Resveratrol (5 or 20 mg/kg) was administered intraperito- neally for 35 days. Rats in the CUMS group and in the 5 mg/kg resveratrol + CUMS group performed poorly in tasks designed to assess emotional and spatial learning and memory. The 20 mg/kg resveratrol + CUMS group showed improved performance compared to the CUMS group. In addition, the CUMS procedure induced lower expression of brain-derived neurotrophic factor and c-Fos in hippocampal CA1 and CA3 and in the amygdala of stressed rats. These effects were reversed by chronic administration of resveratrol (20 mg/kg). In addition, plasma levels of tumor necrosis factor-alpha and interleukin-1 beta were increased by CUMS, but were restored to normal by resveratrol. These results indicate that resveratrol significantly attenuates the deficits in emotional learning and spatial memory seen in chronically stressed rats. These effects may be related to resveratrol-mediated changes in neurotrophin factor expression in hippocampus and in levels of proinflammatory cytokines in circulation. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Chronic stress is an unavoidable life experience that can induce depression [1], impair spatial cognition [2], and cause abnormalities in neuroendocrine function [3] and plasticity [4]. Based on these observations, an animal model of chronic unpredictable mild stress (CUMS) has been developed to mimic the development and progress of stress-associated clinical depression [5] and cogni- tive deficits [6]. It has been proposed that the learning and memory deficits associated with chronic stress may be alleviated using novel therapeutics such as dietary and medicinal phyto-antioxidants. One such nutraceutical is resveratrol. It is a dietary polyphenol found in a wide variety of foods such as berries, nuts, grape skins, and red wine. An increasing research effort is aimed at identifying potential therapeutic roles of resveratrol in human health given its various, and potentially beneficial, antioxidant, anti-inflammatory, and neuroprotective activities [7,8]. Recent studies focusing on the neuroprotective effects of resveratrol have shown that it attenuates amyloid beta peptide- [9,10] and kainic acid-induced toxicities Physiology & Behavior 138 (2015) 297–304 ⁎ Corresponding author at: Experimental Medical Research and Application Centre, Kocaeli University, Kocaeli, Turkey. Tel.: +90 262 3037460; fax: +90 262 303 7003. E-mail address: tijenutkan@hotmail.com (T. Utkan). http://dx.doi.org/10.1016/j.physbeh.2014.10.010 0031-9384/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb