p97 inhibited integrative stress response-induced neuronal apoptosis by enhancing proteasome function after subarachnoid hemorrhage

Abstract Neuronal apoptosis is a common pathological change in early brain injury after subarachnoid hemorrhage (SAH) and is closely associated with neurological deficits. Some research has shown that p97 exhibits a significant anti-cardiomyocyte apoptosis effect. p97 is a key molecule in the growth and development of the nervous system. However, it remains unknown whether p97 can exert an anti-neuronal apoptosis role in SAH disease. We found that p97 was significantly down-regulated in the cerebral cortex of the affected side in mice after SAH. The site of reduced p97 expression was accompanied by a large number of neuronal apoptosis. Adeno-associated virus-mediated over-expression of VCP significantly reduced the number of neuronal apoptosis, improved the early and long-term neurological function, and repaired the neuronal damage in the long term. These neuroprotective effects were accompanied by enhanced proteasome function and inhibition of the integrated stress response (ISR) apoptotic pathway involving eIF2α/CHOP. Administration of the p97 inhibitor NMS-873 resulted in the contrary effect. Subsequently, we observed that inhibiting the function of the proteasome with PS-341 blocked the anti-neuronal apoptosis effect of p97 and enhanced the activation of the ISR apoptotic pathway. However, the detrimental effects of NMS-873 and PS-341 in mice with SAH were counteracted by the administration of the ISR inhibitor ISRIB. These results suggest that p97 can promote neuronal survival and improve neurological function in mice after SAH. The anti-neuronal apoptosis effect of p97 is achieved by promoting the function of the proteasome and further inhibiting the overactivation of the ISR apoptotic pathway.