Endothelin-1 induced cofilin rod formation in hippocampal neurons via endothelin type B receptor and NADPH oxidase-mediated oxidative stress pathway

Abstract

High expression level of endothelin-1 (ET-1) has been detected in the post-mortem brains of Alzheimer’s disease (AD) patients. Two ET receptor (ET rec) subtypes are expressed in neurons. However, the direct effects of ET-1 on mature neurons have remained elusive. ET-1 mediated oxidative stress production via NADPH oxidase (NOX) in endothelial cells, and regulated actin in astrocytes. Previously, oxidative stress-mediated aggregation of cofilin was identified as a key mediator of neuronal degeneration in AD models. Formation of cofilin rods was proposed to mediate the loss of synapses and distal dendrites in primary neurons. Here, this study investigated the effect of ET-1 in mediating cofilin rod formation in 14 days in vitro primary mouse hippocampal neurons. The 24h treatment of ET-1 significantly increased the percentage of neurons with cofilin rods, which was inhibited by pre-treatment of ETB rec antagonist (BQ788), but not by ETA rec antagonist (BQ123). Neurons treated with ETB rec agonist (IRL1620) formed cofilin rods and showed significant reduction of distal dendritic extension. Co- or pre-treatment of antioxidant (N-acetylcysteine) or NOX inhibitor (VAS2870), respectively, inhibited IRL1620-induced cofilin rod formation, indicating ETB rec activation mediated cofilin rod formation via oxidative stress pathway. In short, our findings presented a novel neurotoxic role of ETB rec, associating the ET-1 system dysregulation with AD pathogenesis.