Original research article Effect of trimethylgallic acid esters against chronic stress-induced anxiety-like behavior and oxidative stress in mice Mamta Sachdeva Dhingra a , Sameer Dhingra b , Rachna Kumria c , Renu Chadha a , Tejvir Singh d , Anil Kumar a , Maninder Karan a, * a University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study (UGC-CAS) in Pharmaceutical Sciences, Panjab University, Chandigarh, India b School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago c Swift School of Pharmacy, Swift Group of Colleges, Rajpura, India d Department of Chemistry, UGC Center of Advanced Study (UGC-CAS) in Chemistry, Panjab University, Chandigarh, India Introduction Chronic fatigue stress (CFS) has been reported to produce detrimental effects on human health. Currently, CFS treatment is based on the symptoms and is more of symptomatic nature rather than a cure [1]. Therapies such as cognitive behavior therapy, graded exercise therapy, and pharmacological interventions (e.g. antidepressants and corticosteroids) have been tried, but with limited success. Although these drugs could attenuate the stress in patients [2], the exact mechanism of how these therapies ameliorate fatigue and other related problems have not yet been understood. However, some evidences indicate that CFS is accompanied with signs of increased oxidative stress and inflammation in the peripheral blood, suggesting the involvement of inducible NO synthase (iNOS), inflammation, oxidative and nitrosative stress in the pathogenesis of CFS [3,4]. Further, CFS results in intracellular inflammation, with increased productions of tumor necrosis factor-alpha (TNF-a), interleukin-1 (IL-1) nuclear factor kappa beta (NF-kb), and iNOS. Thus, membrane fatty acids and functional proteins are damaged, due to inflamma- tion, and oxidative and nitrosative stress [5]. A number of factors can trigger the inflammatory, oxidative and nitrosative stress Pharmacological Reports 66 (2014) 606–612 A R T I C L E I N F O Article history: Received 16 June 2013 Received in revised form 20 December 2013 Accepted 13 January 2014 Available online 25 April 2014 Keywords: Trimethylgallic acid esters Chronic stress Chronic fatigue syndrome Antianxiety Neuroinflammation TNF-a A B S T R A C T Background: Many studies have shown that the levels of oxidative stress (increased lipid peroxidation, decreased glutathione levels and endogenous antioxidant enzyme activities) and proinflammatory cytokines (e.g., TNF-a) are increased in patients with chronic fatigue syndrome. Gallic acid and other phenolic compounds are potent antioxidants and inhibitor of cytokine production. The present study was designed to investigate the effect of newly synthesized conjugated esters of trimethylgallic acid in an experimental model of chronic stress. Methods: The animals were forced to swim individually for a period of 6 min every day for 15 days to induce chronic stress. The locomotor activity, anxiety-like behavior, and memory retention were evaluated in chronically stressed animals, followed by biochemical estimations and neuroinflammatory surge in the brain. Results: Chronic treatment with trimethylgallic acid esters for 15 days significantly reversed the chronic stress-induced behavioral (impaired locomotor activity, anxiety-like behavior, and decreased percentage of memory retention), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-a) in stressed mice. Conclusions: The study revealed that trimethylgallic acid esters could ameliorate chronic stress-induced various behavioral and biochemical alterations in mice, showing protective effects against chronic stress. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. Abbreviations: CFS, chronic fatigue stress; IL-1, interleukin-1; COX-2, cyclooxygen- ase-2; ELISA, enzyme-linked immunosorbent assay; FST, forced swim test; GA, gallic acid; IFN-g, interferon gamma; IL-6, interleukin 6; iNOS, inducible nitric oxide synthase; MDA, malondialdehyde; MGG, 2 0 -methoxyphenyl-3,4,5-trimethylgal- late; MRG, 3 0 -hydroxyphenyl-3,4,5-trimethylgallate; MSG, 3 0 ,4 0 -(methylenediox- y)phenyl-3,4,5-trimethylgallate; MUG, 2 0 -oxo-2 0 H-chromene-7 0 -yl-3,4,5- trimethylgallate; NF-kb, nuclear factor kappa beta; nNOS, neuronal nitric oxide synthase; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; TBARS, thiobarbituric acid-reactive substances; TL, transfer latency; TMGA, trimethylgallic acid; TNF-a, tumor necrosis factor-a. * Corresponding author. E-mail address: maninderkaran@hotmail.com (M. Karan). Contents lists available at ScienceDirect Pharmacological Reports jou r nal h o mep ag e: w ww .elsevier .co m /loc ate/p h arep http://dx.doi.org/10.1016/j.pharep.2014.01.004 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.