Metformin Ameliorates Cognitive Impairment and Hippocampal Oxidative Damage in Iron Dextran-induced Oxidative Stress in Male Wistar Rats

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.