CHOP Silencing Reduces Acute Brain Injury in the Rat Model of Subarachnoid Hemorrhage

Abstract

BACKGROUND AND PURPOSE: Endoplasmic reticulum stress triggers apoptotic cascades in neurons of the central nervous system after subarachnoid hemorrhage. The aim of this work was to study the mechanism of neuroprotection conferred by targeting cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the acute brain injury following subarachnoid hemorrhage. METHODS: A total of 172 rats were used. Endovascular perforation induced subarachnoid hemorrhage. Two small interfering RNAs for CHOP were injected 24 hours before hemorrhage induction. At 24 or 72 hours, rats were neurologically evaluated and euthanized. The brains were recovered for molecular biology and histology studies. RESULTS: Western blot analysis revealed effective silencing of CHOP associated with suppression of Bim-Caspase-3 apoptotic pathway. Moreover, the antiapoptotic Bcl2 was found upregulated with CHOP siRNA treatment. A reduced number of TUNEL-positive cells in the subcortex and in the hippocampus reflected histological protection. CHOP siRNA treatment ameliorated intracranial sequelae of and improved functional performance. CONCLUSIONS: We conclude that CHOP silencing alleviates early brain injury following subarachnoid hemorrhage via inhibiting apoptosis and that CHOP siRNA treatment has a clinical potential for patients with this type of hemorrhagic stroke.