Azilsartan Confers Protection Against Kainic Acid–Induced Hippocampal Neuron Damage by Upregulating Sirt3/Sod2 Pathway

Abstract

Epilepsy refers to a diverse group of neurological pathologies, coupled with a significant worldwide impact. Azilsartan, an angiotensin receptor blocker, is broadly applied as an antihypertensive medication. Considering that the neuroprotective potential of Azilsartan has been newly documented, our work was committed to characterizing the association of Azilsartan with epilepsy and its possible mechanism. First, mice hippocampal neuron (HT-22) cells were exposed to kainic acid (KA) with or without Azilsartan treatment. Cell Counting Kit 8 (CCK8) method assessed the viability of KA-treated HT-22 cells. Flow cytometry assay was employed to detect cellular apoptotic capacity. DCF-DA fluorescent staining, JC-1 probe, and related assay kits were used to estimate mitochondrial oxidative stress. Western blotting examined the expression of Sirtuin 3 (Sirt3), superoxide dismutase 2 (Sod2), and apoptosis-related proteins. Additionally, Sirt3 was silenced to analyze whether the protective effect of Azilsartan on KA-induced damage of HT-22 cell damage was achieved by regulating Sirt3. Results indicated that KA intervention concentration-dependently triggered the viability loss, apoptosis, and mitochondrial damage in HT-22 cells. Azilsartan treatment protected against KA-induced HT-22 cell injury by elevating the viability, reducing the apoptosis, and attenuating mitochondrial damage. Besides, Azilsartan administration activated Sirt3 and Sod2 expression in KA-stimulated HT-22 cells, and Sirt3 depletion partially blocked the impacts of Azilsartan on Sirt3/Sod2 pathway, mitochondrial damage, viability, and apoptosis in HT-22 cells exposed to KA. Collectively, Azilsartan might act as a neuroprotective agent in treating epilepsy through the activation of Sirt3/Sod2 pathway.