Neuroprotective impact of nicotinamide riboside and metformin on the hippocampus of male rats with diet-induced obesity.

BACKGROUND: Obesity-induced metabolic disturbances are increasingly recognized as major contributors to hippocampal dysfunction and neurodegeneration. Chronic exposure to a high-fat diet (HFD) has been associated with hippocampal structural alterations, dysregulation of neurotrophic and metabolic signalling, and increased neuronal vulnerability, ultimately impairing cognitive performance. OBJECTIVE: This study investigated the neuroprotective effects of nicotinamide riboside (NR), metformin (MET), and their combination on hippocampal structure, gene expression, and spatial memory in a male rat model of diet-induced obesity. METHODS: Male Wistar rats were assigned to a lean control group or a high-fat diet (HFD) group and maintained on their respective diets for 10 weeks. During the final 4 weeks of the HFD protocol, HFD-fed rats received nicotinamide riboside (NR; 300 mg/kg/day), metformin (MET; 200 mg/kg/day), or their combination by oral gavage while continuing HFD feeding. Stereological analysis was performed to assess hippocampal subregion volumes (CA1 and dentate gyrus), neuronal survival, and total glial cell counts based on morphological criteria. Gene expression levels of Bdnf, Sirt1, Ppargc1a, Bax, Bcl-2, and Casp3 were measured using quantitative real-time PCR (qRT-PCR). Spatial learning and memory were evaluated using the Morris Water Maze (MWM) test. RESULTS: HFD feeding induced obesity accompanied by hippocampal atrophy, altered expression of neurotrophic, metabolic, and apoptosis-related genes, and impaired spatial memory. Treatment with NR and MET, particularly in combination, was associated with attenuation of these alterations. The combination treatment showed the greatest improvement in hippocampal volume, greater neuronal preservation, reduced morphologically identified glial cell counts, and partial normalization of gene expression patterns. Behavioral analysis also indicated better performance in spatial learning and memory, with the NR + MET group showing the most pronounced improvement in escape latency and time spent in the target quadrant. CONCLUSION: NR and metformin were associated with beneficial effects on obesity-related hippocampal alterations, accompanied by favourable changes in apoptosis-related, metabolic, and neurotrophic gene expression as well as improved stereological indices of hippocampal integrity. The combined treatment generally produced greater improvements than either monotherapy. These findings support further investigation of NR and metformin as potential interventions for obesity-associated hippocampal dysfunction and cognitive impairment.