Neuroprotective effect of a Keap1-Nrf2 Protein-Protein Inter-action inhibitor on cerebral Ischemia/Reperfusion injury

Abstract

Oxidative stress has been confirmed to be closely related to the occurrence and development of cerebral ischemic/reperfusion (I/R). The Keap1-Nrf2 pathway is widely recognized as a defensive system to maintain cellular redox homeostasis. Targeting Keap1-Nrf2 interaction by small molecules to release Nrf2 should be a promising strategy to treat cerebral I/R injury. The piperazinyl-naphthalenesulfonamide 6 K was reported to be a Keap1-Nrf2 protein–protein interaction inhibitor, showing promising antioxidative effect. Herein, this study is to investigate whether 6 K could prevent brain from I/R injury. The related mechanism of oxidative stress was also elucidated using in vivo mice middle cerebral artery occlusion (MCAO) model and in vitro SH-SY5Y oxygen-glucose deprivation/reperfusion (OGD/R) model. The results indicated that treatment of 6 K markedly decreased infarct volume, apoptotic neurons and oxidative damage and promoted neurologic recovery in vivo. The cell model revealed that the reactive oxygen species (ROS) was decreased, and cell viability was increased. Western blots and immunofluorescence staining demonstrated that compound treatment promoted Nrf2 release and nuclear translocation. The downstream protective enzymes were significantly enhanced at both in vivo and in vitro levels. Collectively, 6 K is a promising protective agent against cerebral I/R injury through activation of Nrf2 to suppress oxidative stress.