Raj_2026_Eur.J.Pharmacol__178588

Vascular dementia (VaD) is closely associated with metabolic disturbances and endothelial dysfunction. The present study evaluated the effects of eplerenone, a mineralocorticoid receptor antagonist, pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, and fenofibrate, a PPARalpha agonist, administered alone and in combination, in a high-fat diet (HFD)-induced rat model of endothelial dysfunction and VaD. Rats were fed an HFD for 90 days to induce metabolic and vascular alterations. Cognitive performance was assessed using the Morris Water Maze test. Endothelial function was evaluated by measuring endothelium-dependent vasorelaxation in isolated aortic rings and serum nitrite levels. Biochemical markers of oxidative stress, inflammation, and cholinergic function, along with histopathological changes in brain tissue, were also analyzed. HFD feeding resulted in marked endothelial dysfunction, evidenced by impaired vasorelaxation and reduced serum nitrite levels, along with significant cognitive deficits. These changes were accompanied by increased oxidative stress, indicated by elevated thiobarbituric acid reactive substances and reduced glutathione levels, as well as increased acetylcholinesterase and myeloperoxidase activities and neutrophil infiltration in the brain. Treatment with eplerenone, pioglitazone, and fenofibrate, individually and in combination, attenuated endothelial dysfunction, improved cognitive performance, and normalized biochemical and histopathological alterations, with combination therapy showing greater overall efficacy. The novelty of this study lies in its systematic comparison and rational combination of mineralocorticoid receptors (MR) antagonism with PPARalpha and PPARgamma activation in a high-fat diet-induced model of vascular dementia, demonstrating enhanced neurovascular protection with low-dose combination therapy.