Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Full length article An investigation of the effects of metformin on ovarian ischemia-reperfusion injury in rats Atilla Topcu a,* , Gulsah Balik b , Mehtap Atak c , Tolga Mercantepe d , Huseyin Avni Uydu c , Levent Tumkaya d a Recep Tayyip Erdogan University, Faculty of Medicine, Department of Pharmacology, 53100, Rize, Turkey b Recep Tayyip Erdogan University, Faculty of Medicine, Department of Gynecology and Obstetrics, 53100, Rize, Turkey c Recep Tayyip Erdogan University, Faculty of Medicine, Department of Medical Biochemistry, 53100, Rize, Turkey d Recep Tayyip Erdogan University, Faculty of Medicine, Department of Histology and Embryology, 53100, Rize, Turkey ARTICLE INFO Keywords: Ischemia-reperfusion Metformin Ovary Oxidative stress Rat ABSTRACT Damage to the ovaries or tissue torsion can significantly reduce the ovarian reserve and thus cause severe gynecological and hormonal deficiencies. The discovery of new agents is always needed in the treatment of this condition. Metformin (MET) has been shown to be beneficial in attenuating ovarian ischemia-reperfusion injury. Fifty-six female Sprague Dawley rats were divided into seven groups. Group 1 represented the control group (C), Group 2, the ischemia group (I), and Group 3, the ischemia/reperfusion group (I/R). Group 4, the ischemia (I) +250 group, and Group 5, the ischemia (I)+500 group, received 250 mg/kg and 500 mg/kg MET, respectively. Group 6, the ischemia/reperfusion (I/R)+250 group, and Group 7, the ischemia/reperfusion (I/R)+500 group, received 250 mg/kg and 500 mg/kg MET, respectively. Tissue malondialdehyde (MDA), glutathione (GSH), and tumor necrosis factor-alpha (TNF-α) levels in ovarian tissue increased following I/R, while estradiol (E 2 ) levels decreased. Moreover, infiltration and diffuse edematous areas were observed in addition to diffuse vascular congestion and hemorrhage findings. Caspase-3 and nuclear factor kappa B (NF-κβ) expression levels also in- creased. MDA and TNF-α concentrations decreased in the MET treatment groups, while GSH and E 2 levels increased. The findings showed that I/R causes ovarian damage through the induction of oxidative stress, in- flammation, and apoptosis. However, MET application was effective in preventing damage in ovarian tissue by reducing levels of reactive oxygen species, proinflammatory cytokines, caspase-3 and NF-κβ. 1. Introduction Ovarian ischemia represents between 2.5% and 7.4% of surgeries performed on patients presenting to the emergency department due to acute pelvic pain (Huchon and Fauconnier, 2010). It is an important pathological condition requiring emergency gynecological surgery that emerges from restricted blood flow in their vasculature as a result of twisting of their ligaments (Becker and Graaff, 2009; Huchon and Fauconnier, 2010). The principal causes of ovarian torsion are benign ovarian diseases or ovarian cysts, previous surgery in that region, traumas, and pregnancy (Martin, 2006). If the resulting lymphatic and arterial obstruction in the ovary is not eliminated, this leads to edema and bleeding in the ovary, and finally to the emergency condition of necrosis (Yildirim et al., 2018). Necrotic damage in the ovary con- stitutes a significant problem for both young and adult women (Berger and Robbins, 1961; Çelik et al., 2005). Therefore, rapid diagnosis and treatment of ovarian torsion are essential for the preservation of the functioning of the organ (Geimanaite and Trainavicius, 2013). Ovarian torsion first exhibits abdominal pain, which must be dif- ferentiated from other conditions by ultrasonography and colored Doppler ultrasonography before surgical intervention for detorsion or ovariectomy (Dolgin et al., 2000; Kolusari, 2010; Lee et al., 1998; Moravec et al., 1980). Surgical restoration of blood flow is not entirely curative in the treatment of ovarian torsion and leads to the onset of a more painful pathological process known as reperfusion damage (Somuncu et al., 2008). Ischemia in ovarian tissue results in lower energy consumption and increase in toxic metabolite accumulation in cells, which further ex- acerbate the scale of the damage. Reoxygenation of the tissue results in an increase in reactive oxygen species (ROS)(Halici et al., 2008). Re- active oxygen species oxidise membrane lipids to form mal- ondialdehyde (MDA). Therefore, MDA is an important marker for https://doi.org/10.1016/j.ejphar.2019.172790 Received 1 August 2019; Received in revised form 4 November 2019; Accepted 7 November 2019 * Corresponding author.Recep Tayyip Erdogan University, Faculty of Medicine, Department of Pharmacology, Rize, 53100, Turkey. E-mail address: atilla.topcu@erdogan.edu.tr (A. Topcu). European Journal of Pharmacology xxx (xxxx) xxxx 0014-2999/ © 2019 Elsevier B.V. All rights reserved. Please cite this article as: Atilla Topcu, et al., European Journal of Pharmacology, https://doi.org/10.1016/j.ejphar.2019.172790