Attenuation of cerebral ischemia-reperfusion induced neurotoxicity by telmisartan, ertugliflozin, and omaveloxolone through Nrf2/HO-1 pathway modulation: In vivo and in silico insights

Ischemia-reperfusion (IR) injury in the brain is a major cause of brain damage and neurotoxicity, particularly in patients with hypertension and diabetes, where oxidative stress and inflammation play critical roles. This study investigated the effects of telmisartan, ertugliflozin and omaveloxolone, on cerebral ischemia reperfusion IR-induced damage and neurotoxicity through modulation of the nuclear factor erythroid 2–related factor 2/ heme oxygenase-1 (Nrf2/HO-1) signaling pathway. Forty-two rats were divided into seven groups, including controls and treatment groups that received the drugs before ischemia induction via bilateral common carotid artery occlusion (BCCAO) followed by reperfusion. All three agents markedly enhanced Nrf2 immunoreactivity through immunohistochemical analysis and heme oxygenase-1 (HO-1) gene expression in brain tissues compared to controls. They also attenuated neurotoxic outcomes by reducing histopathological damage and lowering inflammatory mediators such as Nuclear Factor kappa-B (NF-κB), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Matrix Metalloproteinase-9 (MMP-9). A significant negative correlation was observed between Nrf2 activation and the severity of neurotoxicity inflammatory markers. In silico analysis revealed strong binding through highly negative docking scores of telmisartan and ertugliflozin to Nrf2 negative regulators Keap1 and GSK-3β, supported by stable molecular dynamics simulations, suggesting direct inhibition. In conclusion, omaveloxolone, telmisartan, and ertugliflozin alleviate ischemia-reperfusion induced neurotoxicity via potential Nrf2-mediated antioxidant and anti-inflammatory mechanisms, highlighting their potential preventive role in conditions predisposing to stroke. • Telmisartan, ertugliflozin, and omaveloxolone could activate the Nrf2/HO-1 signaling axis, mitigating cerebral ischemia-reperfusion-induced neurotoxicity. • All studied pretreatments significantly decrease levels of inflammatory markers in brain tissues. • Histopathological Improvement, observed reduction in neuronal damage post-treatment. • In Silico Validation confirm strong binding affinities of telmisartan and ertugliflozin to Nrf2 regulators. • Findings suggest potential repurposing of these agents for stroke prevention in at-risk populations.