Teneligliptin protects against ischemia/reperfusion-induced endothelial permeability in vivo and in vitro

Abstract

Ischemic stroke is a leading cause of disability and mortality worldwide, especially among the elderly population. Ischemia and reperfusion cause damage to cells and initiate an acute inflammatory response, which leads to cerebral endothelial dysfunction, increased endothelial permeability, and potentially permanent disability. Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been used almost exclusively in the treatment of type 2 diabetes mellitus. However, it is still unknown whether teneligliptin possesses a protective effect in brain endothelial dysfunction in the context of ischemic stroke. In the present work, we demonstrate the potential of teneligliptin treatment to protect against ischemia/reperfusion-induced damage using a series of both in vivo and in vitro experiments. Our key findings are that administration of teneligliptin could reduce brain infarct volume, ameliorate neurological damage, and improve brain permeability by increasing the expression of the tight junction protein occludin in middle cerebral artery occlusion (MCAO) mice models. Importantly, teneligliptin displayed a robust protective effect against oxygen–glucose deprivation/reperfusion (OGD/R)-induced cell death of primary human brain microvascular endothelial cells (HBMVECs) in vitro. Notably, teneligliptin prevented OGD/R-induced increased endothelial monolayer permeability in HBMVECs by increasing the expression of occludin, which was mediated by the ERK5/KLF2 signaling pathway. These findings suggest that teneligliptin might serve as a potential therapeutic agent for the treatment of stroke