Le, Dean A.Wu, YongqinHuang, ZhihongMatsushita, KohjiPlesnila, NikolausAugustinack, Jean C.Hyman, Bradley T.Yuan, JunyingKuida, KeisukeFlavell, Richard A.Moskowitz, Michael A.2019-10-052002Le, D. A., Y. Wu, Z. Huang, K. Matsushita, N. Plesnila, J. C. Augustinack, B. T. Hyman, et al. 2002. “Caspase Activation and Neuroprotection in Caspase-3- Deficient Mice after in Vivo Cerebral Ischemia and in Vitro Oxygen Glucose Deprivation.” Proceedings of the National Academy of Sciences 99 (23): 15188–93. https://doi.org/10.1073/pnas.232473399.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41483515Caspase-3 is a major cell death effector protease in the adult and neonatal nervous system. We found a greater number and higher density of cells in the cortex of caspase-3(-/-) adult mice, consistent with a defect in developmental cell death. Caspase-3(-/-) mice were also more resistant to ischemic stress both in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical infarct volume was reduced by 55%, and the density of terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells was decreased by 36% compared with wild type. When subjected to oxygen-glucose deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3 expression were also more resistant to cell death by 59%. Mutant brains showed caspase-specific poly(ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase-mediated cell death. In the present study, we found that caspase-8 mediated poly(ADP-ribose) polymerase cleavage in caspase-3(-/-) neurons in vivo and in vitro. In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the pharmacological evidence supporting an important role for caspase-3 and caspase-8 as cell death mediators in mammalian cortex and indicate the potential advantages of targeting more than a single caspase family member to treat ischemic cell injury.en-USJournal Article2019-10-0510.1073/pnas.232473399