Notch1-dependent hippocampal apoptosis is associated with monocrotaline-induced anxiety-like behavior.

Abstract

Monocrotaline (MCT), an alkaloid from the genus Crotalaria, is widely used to establish an animal model of pulmonary hypertension. The toxicity of MCT extends not only to peripheral organs but also to the nervous system. However, the molecular mechanism responsible for the development of anxiety disorders after MCT poisoning remains unclear. MCT (60 mg/kg) administration for 4 weeks was used to induce a rat model of anxiety-like behavior with pulmonary hypertension. Open field and elevated plus maze tests showed MCT increased anxiety-like behavior in rats with pulmonary hypertension. Hematoxylin and eosin staining of the hippocampus and annexin V-FITC/PI staining of the mouse hippocampal cell line HT22 with MCT infusion showed that MCT promoted apoptosis in hippocampal neurons. The western blot showed MCT increased the apoptosis effector caspase-3 expression and activation in vivo and in vitro. Simultaneously, Notch1 and its downstream gene expression were also increased in vivo and in vitro. Furthermore, Notch1 deletion with siRNA can eliminate MCT-induced apoptosis and caspase-3 expression and activation. The Notch1 inhibitor DAPT has the same effect in vitro. In addition, DAPT alleviated MCT-induced anxiety-related behavior and attenuated hippocampal apoptosis in vivo. The present study reveals that the mechanism of MCT-induced neurotoxic effects in hippocampal neurons is mediated by the Notch1/caspase-3 pathway.