Inhibition of BECN1 Suppresses Lipid Peroxidation by Increasing System Xc- Activity in Early Brain Injury after Subarachnoid Hemorrhage.

Lipid peroxidation plays a crucial role in early brain injury (EBI) after subarachnoid hemorrhage (SAH), and cystine/glutamate antiporter system X_c^- has been proved to be associated with glutathione (GSH) synthesis, which protects cells against oxidative damage. Antioxidant effect of system X_c^- is mediated by Beclin 1 (BECN1). Therefore, this study aimed to determine whether administration of BECN1 small interfering RNA (siRNA) could attenuate EBI after SAH experiment, specifically through suppressing lipid peroxidation and increasing system X_c^- activity. Endovascular perforation was performed to induce SAH in a rat model and BECN1 siRNA was administered through intracerebroventricular injection. Neurological score, brain edema, lipid peroxidation (malondialdehyde, MDA), and antioxidation system, containing GSH, glutathione peroxidase (GSH-Px), glutathione reductase (GR), and anti-reactive oxygen species (anti-ROS), were examined. The expression of BECN1 and light chain of system X_c^- (xCT) was detected by western blot, immunoprecipitation, and immunofluorescence staining. This study confirmed that SAH induced neurological deficits and brain edema, which was accompanied by the increase of BECN1 expression and lipid peroxidation, and the decrease of xCT expression and antioxidative capacity. However, downregulation of BECN1 by siRNA could decrease the formation of the BECN1-xCT complex and lipid peroxidation, enhance antioxidative capacity, and ameliorate neurological deficits and brain edema in SAH rats. The results suggested that inhibition of BECN1 suppresses accumulation of lipid peroxidation by increasing system X_c^- activity in EBI after SAH, and BECN1 may be a new effective target for EBI treatment after SAH.