127 Siramesine Attenuates Early Brain Injury through TMEM97/NPC1 Pathway After Experiment Subarachnoid Hemorrhage in Rats

INTRODUCTION: Early brain injury (EBI) has been confirmed as the primary determinant of poor outcomes in SAH. Cell apoptosis and oxidative stress may be critical to the development of EBI. Excessive mitochondrial fission directly induces in cell oxidative stress and apoptosis. However, the regulatory mechanisms remain unknown. We found that Sigma-2/Transmembrane protein 97 (TMEM97) protein may be involved in the process. METHODS: A total of 187 rats were used. Siramesine was administered intraperitoneally 1 h after SAH induction. SM-21, an antagonist of TMEM97, and small interfering ribonucleic acid (siRNA) for NPC1 were administered by intraperitoneally or intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Western blot, immunofluorescence, the mortality, SAH grade, neurological tests, Fluoro-Jade C, Nissal staining, water maze, balance fatigue rotarod test and DHE staining were performed. RESULTS: The expression of TMEM97 protein decreased after SAH. Siramesine improves neurological functional deficits in SAH rats, while also reducing oxidative stress response and apoptosis. Siramesine upregulates the expression of TMEM97, NPC1, DJ-1, and anti-apoptotic protein Bcl-2, while downregulating the expression of Drp1, Roma-1 and Bax. Effect of Siramesine was weakened after the application of SM-21 and NPC1 siRNA. The protective effects of Siramesine were reversed by i.p. injection of SM-21 and NPC1 siRNA. CONCLUSIONS: Oxidative stress and apoptosis were related to early brain injury in SAH rats. TMEM97/NPC1 signaling pathway was involving in the regulating the process of early brain injury. The activation of TMEM97/NPC1 signaling pathway can reduce neuronal oxidative stress and apoptosis after SAH in rats. Siramesine can reduce oxidative stress and apoptosis through TMEM97/NPC1 pathway after SAH.