Pumpkin seed oil protects against diabetes-induced cognitive impairment through modulation of oxidative stress, Aβ/BACE-1, and apoptosis-related signaling

Pumpkin seed oil (PSO) has been reported to improve metabolic dysfunction in type 2 diabetes mellitus (T2DM); however, its potential neuroprotective mechanisms in diabetes-associated cognitive impairment remain insufficiently characterized. In the present study, we conducted a systematic in vivo evaluation to determine whether PSO alleviates diabetes-related cognitive dysfunction through coordinated modulation of multiple pathogenic pathways. Male Sprague–Dawley rats were assigned to four groups: normal control (CON), T2DM, T2DM treated with pioglitazone (T2DM-PG), and T2DM treated with PSO (200 mg/kg B.W.). During a 15-week experimental period, metabolic parameters, cognitive performance using the novel object recognition (NOR) and Morris water maze (MWM) tests, hippocampal amyloidogenic markers (Aβ42 and BACE-1), oxidative stress indicators (MDA, SOD, and Nrf2), and apoptosis-related proteins (Bax, procaspase-3, and Bcl-2) were evaluated. PSO administration significantly improved glycemic control, lipid profile, insulin sensitivity, and cognitive performance in T2DM rats. These functional improvements were accompanied by reduced hippocampal Aβ42 accumulation and BACE-1 expression, attenuation of oxidative stress characterized by decreased MDA levels and increased SOD activity and Nrf2 expression, and modulation of apoptosis-related signaling toward a less pro-apoptotic profile. Collectively, these findings indicate that PSO may mitigate diabetes-associated cognitive impairment through integrated regulation of metabolic dysfunction, oxidative stress, and amyloid-related alterations, together with modulation of apoptosis-related-signaling pathways.This study provides mechanistic insight into the neuroprotective potential of PSO and highlightings its potential relevance as a functional food–derived bioactive agent in diabetes-associated cognitive impairment. • Pumpkin seed oil improved metabolic dysfunction and cognitive performance in T2DM rats. • PSO reduced hippocampal Aβ42 accumulation and BACE-1 expression. • PSO was associated with reduced oxidative stress via the Nrf2 pathway. • PSO modulated apoptosis-related signaling by restoring Bax/Bcl-2 balance. • PSO showed multi-target effects in diabetes-associated cognitive impairment.