Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet Kalivarathan Jagan, Chandrasekaran Sathiya Priya, Kalaivanan Kalpana, Ramachandran Vidhya, Carani Venkatraman Anuradha* Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar 608 002, Tamil Nadu, India A R T I C L E I N F O Article history: Received 23 November 2016 Received in revised form 23 January 2017 Accepted 29 January 2017 Keywords: High calorie diet Hippocampus Oxidative stress Inflammation Apigenin Sitagliptin A B S T R A C T High calorie diet promotes oxidative stress and chronic low grade inflammation that predispose to brain dysfunction and neurodegeneration. Hippocampus region of the brain has been shown to be particularly sensitive to high calorie diet. We hypothesize that apigenin (API), a flavonoid could attenuate hippocampal derangements induced by high fat-high fructose diet (HFFD). In this study, we investigated the effects of API on oxidative stress and inflammation in the hippocampus, and compared with those of sitagliptin (STG), a standard drug with neuroprotective properties. The markers of oxidative stress and inflammation were examined using biochemical assays, western blotting and immunohistochemistry techniques. HFFD-fed rats showed severe pathological alterations and API treatment rescued the hippocampus from the derangements. API significantly improved the antioxidant machinery, reduced ROS levels and prevented the activation of the stress kinases, inhibitor of kappa B kinase beta (IKKb) and c-Jun NH2 terminal kinase (JNK), and the nuclear translocation and activation of nuclear factor kappa B (NF-kB). The plasma levels of inflammatory cytokines were also reduced. Our findings suggest that hippocampal derangements triggered by HFFD feeding were effectively curtailed by API. Suppression of oxidative stress, NF-kB activation and JNK phosphorylation in the hippocampus are the mechanisms by which API offers neuroprotection in this model. © 2017 Elsevier Masson SAS. All rights reserved. 1. Introduction Intake of calorie-abundant foods is steadily on the rise in parallel with an escalating incidence of metabolic diseases such as obesity and type 2 diabetes (T2D). Calorie rich diet provides excess fats and sugars creating a stress on the metabolic machinery. Recent research provides evidence for the adverse effects of high calorie diet on brain functions which can increase the susceptibili- ty to neurodegenerative disorders [1]. Hippocampal region of the brain is important for learning and memory and is the most sensitive to metabolic changes associated with dietary habits. High-calorie diet impairs the structure and function of the hippocampus causing a decline in neurogenesis, synaptic plasticity and cognition [2]. Cells suffer from oxidative stress when there is an imbalance between free radical production and cellular antioxidant defense mechanisms. The brain tissue is highly susceptible to oxidative insults because of its high oxygen consumption rate, abundant lipid content and relative paucity of antioxidant enzymes. Many studies show that reactive oxygen species (ROS) production in the neuronal cells plays an important role in neurodegenerative disorders [3]. Inflammation is recognized to be yet another causative mechanism that facilitates neuronal dysfunction and neuro- degeneration. Nuclear factor-kB (NF-kB) signaling and c-Jun NH2 terminal kinase (JNK) activation are suggested to be involved in the pathology of brain inflammation leading to neuronal apoptosis, neuronal loss and impaired cognition [4]. ROS can promote inflammation by activating cellular JNK and another kinase called inhibitor of kappa B kinase beta (IKKb). Activation of Abbreviations: HFFD, high fat-high fructose diet; API, apigenin; STG, sitagliptin; IKKb, inhibitor of kappa B kinase beta; NF-kB, nuclear factor kappa B; JNK, c-Jun NH2 terminal kinase; T2D, type 2 diabetes; TNF-a, tumour necrosis factor-a; IL-6, interleukin-6; 3-NT, 3-nitrotyrosine; 4-HNE, 4-hydroxynonenol; TBARS, thiobarbi- turic acid reactive substances; LHP, lipid hydroperoxides; PCO, protein carbonyl; AOPP, advanced oxidation protein products; FRAP, ferric reducing antioxidant power; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidise; GSH, reduced glutathione. * Corresponding author. E-mail address: cvaradha@yahoo.com (A. Carani Venkatraman). http://dx.doi.org/10.1016/j.biopha.2017.01.162 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved. Biomedicine & Pharmacotherapy 89 (2017) 323–331 Available online at ScienceDirect www.sciencedirect.com