@article {Chen4914, author = {Jun Chen and Tetsuya Nagayama and Kunlin Jin and R. Anne Stetler and Raymond L. Zhu and Steven H. Graham and Roger P. Simon}, title = {Induction of Caspase-3-Like Protease May Mediate Delayed Neuronal Death in the Hippocampus after Transient Cerebral Ischemia}, volume = {18}, number = {13}, pages = {4914--4928}, year = {1998}, doi = {10.1523/JNEUROSCI.18-13-04914.1998}, publisher = {Society for Neuroscience}, abstract = {Delayed neuronal death after transient cerebral ischemia may be mediated, in part, by the induction of apoptosis-regulatory gene products. Caspase-3 is a newly characterized mammalian cysteine protease that promotes cell death during brain development, in neuronal cultures, and in other cell types under many different conditions. To determine whether caspase-3 serves to regulate neuronal death after cerebral ischemia, we have (1) cloned a cDNA encoding the rat brain caspase-3; (2) examined caspase-3 mRNA and protein expression in the brain using in situ hybridization, Northern and Western blot analyses, and double-labeled immunohistochemistry; (3) determined caspase-3-like activity in brain cell extracts; and (4) studied the effect of caspase-3 inhibition on cell survival and DNA fragmentation in the hippocampus in a rat model of transient global ischemia. At 8{\textendash}72 hr after ischemia, caspase-3 mRNA and protein were induced in the hippocampus and caudate-putamen (CPu), accompanied by increased caspase-3-like protease activity. In the hippocampus, caspase-3 mRNA and protein were predominantly increased in degenerating CA1 pyramidal neurons. Proteolytic activation of the caspase-3 precursor was detected in hippocampus and CPu but not in cortex at 4{\textendash}72 hr after ischemia. Double-label experiments detected DNA fragmentation in the majority of CA1 neurons and selective CPu neurons that overexpressed caspase-3. Furthermore, ventricular infusion of Z-DEVD-FMK, a caspase-3 inhibitor, decreased caspase-3 activity in the hippocampus and significantly reduced cell death and DNA fragmentation in the CA1 sector up to 7 d after ischemia. These data strongly suggest that caspase-3 activity contributes to delayed neuronal death after transient ischemia.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/18/13/4914}, eprint = {https://www.jneurosci.org/content/18/13/4914.full.pdf}, journal = {Journal of Neuroscience} }