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This study aimed to investigate the possible ameliorative effects of co-supplementation with Mg2+ and treadmill exercise on memory deficit in aged rats. Fifty male albino rats (10 young and 40 aged rats) were divided into 5 groups (10 rats/group): young, aged sedentary, aged exercised, aged Mg2+-supplemented, and aged exercised and Mg2+-supplemented. Memory was assessed using the Y-maze and novel object recognition tests. Plasma samples were collected for measurement of C-reactive protein (CRP). Subsequently, brain malondialdehyde and catalase levels were measured. Histological and immunohistochemical analyses of the hippocampi were performed. Our results showed impaired memory in aged sedentary rats, with significantly elevated plasma CRP and brain malondialdehyde levels and decreased brain catalase. The hippocampus of aged sedentary rats showed cellular degeneration, downregulation of synaptophysin (SYP) and proliferating cell nuclear antigen (PCNA), and upregulation of glial fibrillary acidic protein (GFAP) and caspase-3. Mg2+ supplementation and/or treadmill exercise significantly improved memory tests in aged rats, which could be explained by the upregulation of hippocampal SYP and PCNA expression and downregulation of GFAP and caspase-3 expression with antioxidant and anti-inflammatory mechanisms. The combined therapy had a better effect than both treatments alone, confirming the role of Mg2+ supplementation with physical exercise in enhancing age-related memory deficit. Novelty: Magnesium supplementation with treadmill exercise improves memory deficit in aged rats. The possible mechanisms are upregulation of the hippocampal synaptophysin and PCNA, downregulation of GFAP and caspase-3, the antioxidant and anti-inflammatory mechanisms.

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