Azilsartan prevents central modulation of BDNF and PPARγ in Alzheimer's pathology through amyloidogenic and inflammatory pathways: experimental and computational evidence.

Abstract

Complex progressive neurodegenerative Alzheimer's disease is characterized by cognitive decline, memory impairment, and accumulation of amyloid and tau pathologies, along with aggravation of neuroinflammatory and oxidative stress pathways. In our previous studies, the potential of azilsartan, a widely used angiotensin receptor blocker (ARB), was demonstrated to possess neuroprotective action when administered through intranasal route, improving memory and cognition through modulation of central renin-angiotensin signalling in a demented animal model. With the intranasal administration, azilsartan nanoemulgel offers the ability to bypass the BBB due to the use of the olfactory and trigeminal neural pathways, achieving direct brain targeting of the therapeutics. In the present study, the neuroprotective effect of azilsartan (5 mg/kg via intranasal route consequently for 45 days) was further validated in an AlCl-induced murine model of Alzheimer's dementia through investigation of mechanistic pathways. The results demonstrated that intranasal delivery of azilsartan significantly ameliorated cognitive decline when compared to standard drug donepezil, as evidenced from the behavioural tests, restored hippocampal oxidative balance (SOD, GSH, CAT), reduced lipid peroxidation (2.6-fold reduction in MDA levels compared to the AlCl-intoxicated group), and increased neuronal count. The biomarker study revealed suppression of inflammatory markers, reduction of Alzheimer's specific pathological markers, and significant restoration of neurotrophic pathways. To validate these findings, in silico molecular docking and dynamics simulations were conducted on the key markers TNFα, IL1β, PPARγ, BDNF, APP, and p-Tau, which showed strong and stable binding interactions with BDNF and PPARγ and moderate but persistent stabilization with APP and p-Tau, aligning with in vivo experimental outcomes. Therefore, the integrated computational and experimental evidence thus demonstrates that azilsartan exhibits neuroprotection, highlighting its potential as a therapeutic candidate for repurposing in Alzheimer's disease.