Objective: Secondary brain injury after subarachnoid hemorrhage (SAH) is poorly understood. As a result, there are few treatment options. Consequently, SAH is associated with a high rate of morbidity and mortality. In an effort to combat these problems, the role of apoptosis was examined in the whole brain after SAH. In particular, the role of p53 and the three major apoptotic cascades were studied, the caspase-dependent and caspase-independent cascades and the mitochondrial pathway.
Methods: In this study, 195 Sprague-Dawley rats were divided into three groups, including sham, nontreatment, and treatment (Pifithrin-alpha; BIOMOL, Inc., Plymouth Meeting, PA) groups. The monofilament puncture model was used to induce SAH and the animals were subsequently sacrificed at 24 and 72 hours. Western blot analysis, histology, physiological parameters, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, and immunohistological techniques were used to demonstrate the role of p53 and the apoptotic cascades in the rat brain after SAH. In addition, outcome was determined based on mortality rates and neurological outcome scores.
Results: We found that p53 and associated apoptotic proteins were up-regulated after SAH and that downstream mediators of apoptosis were negatively influenced by the inhibition of p53 by Pifithrin-alpha. Furthermore, we found that apoptotic inhibition resulted in less cell death and an overall favorable outcome in the treated animals.
Conclusion: These results suggest that apoptosis may be an important cause of cell death in the brain after SAH and that p53 may play an orchestrating role regarding apoptosis in SAH.