Simvastatin reduces caspase-3 activation and inflammatory markers induced by hypoxia-ischemia in the newborn rat.

The present study was undertaken to evaluate whether in a neonatal model of stroke a prophylactic neuroprotective treatment with simvastatin modulates hypoxia-ischemia-induced inflammatory and apoptotic signaling. Procaspase-3 and cleaved caspase-3 expression showed a peak at 24 h and returned to control values after 5 days. Caspase-3 activity followed the same pattern of caspase-3 proteolytic cleavage. In simvastatin-treated ischemic animals, the expression of these proteins and caspase-3 activity were significantly lower when compared to that of ischemic animals. alpha-Spectrin and protein kinase C-alpha (PKCalpha) cleavages were not affected by the treatment. Poly (ADP-ribose) polymerase fragmentation, caspase-1 activation, and IL-1beta and ICAM-1 mRNA expression were increased by hypoxia-ischemia and significantly reduced in simvastatin-treated animals. The results indicate that simvastatin-induced attenuation of hypoxia-ischemia brain injury in the newborn rat occurs through reduction of the inflammatory response, caspase-3 activation, and apoptotic cell death.