Metformin Ameliorates Cognitive Impairment and Hippocampal Oxidative Damage in Iron Dextran-induced Oxidative Stress in Male Wistar Rats
Uduak A. Inwang *
Department of Physiology, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu Alike, Nigeria.
Daisy Dominic
Department of Nursing, Faculty of Nursing Sciences, Niger Delta University, Wilberforce Island, Amassoma, Bayelsa State, Nigeria.
Kubiat T. Umana
Department of Physiology, Faculty of Basic Medical Sciences, University of Uyo, Uyo, Nigeria.
Nze P. Odunnaya
Department of Physiology, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu Alike, Nigeria.
Emmanuel O. Nwuzor
Department of Medical Biochemistry, Faculty of Basic Medical Sciences, David Umahi Federal University (DUFUHS), Uburu,Ebonyi State, Nigeria and International Institute for Infectious Diseases, Biosafety and Biosecurity Research, (DUFUHS), Uburu, Ebonyi State, Nigeria.
Peter O. Odu
Department of Physiology, Faculty of Basic Medical Sciences, University of Calabar, Calabar, Cross River State, Nigeria.
Bakumor S. Yolo
Department of Pharmacology, Faculty of Basic Clinical Sciences, Alex Ekwueme Federal University, Ndufu Alike, Nigeria.
Emmanuel I. Obi
Department of Pharmacology, Faculty of Basic Medical Sciences, University of Calabar, Cross River, Nigeria and Department of Community Medicine, National Obstetric Fistula Centre, Abakaliki, Nigeria.
Lekara John
Department of Animal and Environmental Biology, Faculty of Natural and Applied Sciences, Ignatius Ajuru University, Port Harcourt, Rivers State, Nigeria.
*Author to whom correspondence should be addressed.
Abstract
Metformin, a first-line therapy for type 2 diabetes mellitus, is increasingly recognised for pleiotropic effects beyond glycaemic control, including potential neuroprotection. However, whether metformin protects cognition under mild iron-related oxidative stress remains unclear. This preclinical study investigated the effects of metformin on cognitive and hippocampal alterations in a rat model of mild iron-induced stress. Twenty-four adult male Wistar rats were randomly divided into four groups: control; metformin only (200 mg/kg orally once daily for 14 days); iron only (iron dextran 5 mg/kg intraperitoneally once daily for 7 days); and iron plus metformin (iron dextran 5 mg/kg for 7 days plus metformin 200 mg/kg orally once daily for 14 days). Spatial working memory was assessed by the Y-maze spontaneous alternation test. Hippocampal glutathione peroxidase (GPx) activity was measured, and hippocampal histology was evaluated by haematoxylin and eosin staining. Iron-only rats showed a significant reduction in percentage alternation (48.9%) compared with controls (72.5%). Metformin-only rats exhibited markedly increased alternation (76.06%), whereas iron-plus-metformin rats showed partial recovery (68.24%) compared with iron-only rats. Iron decreased hippocampal GPx activity (19.04 U/mg), while metformin co-treatment increased GPx activity (32.14 U/mg) relative to iron alone. Histologically, iron-only rats displayed karyorrhexis in most hippocampal pyramidal cells, whereas iron-plus-metformin rats showed distinct pyramidal neurons within the pyramidal cell layer, comparable to control and metformin-only groups. Overall, these findings suggest that metformin attenuates mild iron-induced cognitive impairment and hippocampal injury in male Wistar rats, possibly through antioxidant and neuroprotective mechanisms.
Keywords: Metformin, iron-induced stress, cognition, hippocampus, glutathione peroxidase, oxidative stress, neuroprotection, catalase, antioxidant defence, hippocampal histology