Bax inhibitor-1 suppresses early brain injury following experimental subarachnoid hemorrhage in rats

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is an important cause of high mortality and poor prognosis in SAH. B-cell lymphoma 2-associated X protein inhibitor-1 (BI-1) is an evolutionarily conserved anti-apoptotic protein that is primarily located in the membranes of endoplasmic reticulum (ER). BI-1 has been studied in certain nervous system-associated diseases, but the role of this protein in SAH remains unclear. In the present study, the role of BI-1 in EBI following SAH was investigated in rat models and its associated mechanisms were examined. The SAH rat model was generated by inserting nylon cords into the internal carotid artery from the external carotid artery. Samples were assessed using neurological scores, brain water content measurements, hematoxylin and eosin (H&E) staining, blood-brain barrier (BBB) permeability, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and quantitative polymerase chain reaction assays, and western blot analyses. It was identified that the mRNA and protein levels of BI-1 decreased markedly and were lowest at 24 h after SAH. BI-1 overexpression and small hairpin RNA (shRNA)-mediated silencing markedly suppressed or severely exacerbated EBI following SAH, respectively. BI-1 over-expression in the SAH model improved neurological scores and decreased the brain water content, BBB permeability and levels of apoptosis compared with the control and sham groups following SAH. BI-1 shRNA in the SAH model demonstrated contrary results. In addition, the mRNA or protein expression levels of ER stress-associated genes (glucose regulated protein, 78 kDa, C/EBP homologous protein, Serine/threonine-protein kinase/endoribonuclease IRE1, c-Jun N terminal kinases and apoptotic signaling kinase-1) were markedly suppressed or increased following BI-1 overexpression and shRNA-mediated silencing, respectively. The present study suggested that BI-1 serves a neuroprotective role in EBI following SAH by attenuating BBB disruption, brain edema and apoptosis mediated by ER stress.