Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Research article The effect of the anti-diabetic drug metformin on behavioral manifestations associated with ovariectomy in mice Iman Fatemi a,b , Fatemeh Delrobaee c , Maryam Bahmani c , Ali Shamsizadeh a,b , Mohammad Allahtavakoli a,b, ⁎ a Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran b Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran c Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran ARTICLE INFO Keywords: Ovariectomy Metformin Anxiety Cognition ABSTRACT The aim of this study was to evaluate the anti-diabetic drug metformin (Met) effects on the anxiety and cognitive impairment in ovariectomized mice. Thirty-two female adult mice were distributed into four groups: control, sham ovariectomy, ovariectomy + Met 7 mg/kg and ovariectomy + Met 15 mg/kg. The vaginal cytology was used to confirm the ovariectomy surgery. Anxiety was monitored using elevated plus maze test and cognitive function was assessed by novel object recognition task. Animal’s brains were analyzed for the brain-derived neurotrophic factor (BDNF). Our results demonstrated that ovariectomy caused cognitive impairments and anxiety, as well as decreased BDNF levels. Moreover, administration of Met improves ovariectomy-related dis- orders such as cognitive impairments and anxiety, as well as increased BDNF levels. The results of the present study suggest that Met could be used as a novel therapeutic strategy for the treatment of ovariectomy-related conditions. 1. Introduction It is expected that the global population of menopausal women will increase over 1.2 million by the year 2030 [5]. Menopause is defined by the loss of ovarian follicular activity and decline in gonadal hormones in the females [1,18]. After menopause women usually suffer from menopausal symptom including tender breasts, low bone density, hot flushes, cognitive decline and anxiety [32]. It has been demonstrated that gonadal hormones play an important role in mood and cognition; and sex hormones deficiency is related with anxiety and cognition impairment in menopause [7]. It is well demonstrated that Brain-de- rived neurotrophic factor (BDNF) levels decrease in the ovariectomized rat which contributed to cognition impairment [10]. Hormone re- placement therapy is considered as a therapeutic intervention in an- xiety and cognitive impairments, particularly after menopause in women [34]. Nevertheless, clinically administration of these hormones especially estrogen has controversy due to the fact that long-term consumption of it may increase the risk of endometrial and breast cancer development in women [39]. Metformin (Met) is recommended as the first-line drug in patients with type 2 diabetes which reduces hyperglycemia via improving glu- cose utilization and synthesis [12,23]. This drug has also been reported that has pleiotropic effects including anti-inflammatory, antioxidant and neuroprotective effects which may extend its clinical indications [2,25]. It is well established that Met passes the blood-brain barrier and distributes within CNS [27]. Furthermore, several studies have reported the positive effects of this agent on behavioral disorders such as anxiety and cognitive impairment [1,3,13,14]. Due to behavioral manifestations associated with ovariectomy and the effects of Met on behavioral disorders, we hypothesized that Met may has positive effects on anxiety-like behavior and cognitive im- pairment in ovariectomized (OVX) mice. For this purpose, we compared the anxiety-like behavior, cognitive impairment and BDNF levels of sham and OVX mice with or without Met treatment by elevated plus- maze (EPM) and the novel object recognition task (NORT). 2. Materials and methods 2.1. Animals In this study 32 female mice (22–27 g) were kept under standard laboratory conditions with food and water ad libitum and housed 8 per cage on a reversed 12-h light: 12-h dark cycle. The experiments were done base on the Animal Ethics Committee Guidelines for the use of https://doi.org/10.1016/j.neulet.2018.10.024 Received 1 July 2018; Received in revised form 6 October 2018; Accepted 11 October 2018 ⁎ Corresponding author at: Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, 7717684884, Iran. E-mail address: m_alahtavakoli@rums.ac.ir (M. Allahtavakoli). Neuroscience Letters 690 (2019) 95–98 Available online 12 October 2018 0304-3940/ © 2018 Published by Elsevier B.V. T