Caspase-3 mediated neuronal death after traumatic brain injury in rats

During programmed cell death, activation of caspase-3 leads to proteolysis of DNA repair proteins, cytoskeletal proteins, and the inhibitor of caspase -activated deoxyribonuclease, culminating in morphologic changes and DNA da mage defining apoptosis, The participation of caspase-3 activation in the e volution of neuronal death after traumatic brain injury in rats was examine d. Cleavage of pro-caspase-3 in cytosolic cellular fractions and an increas e in caspase-3-like enzyme activity were seen in injured brain versus contr ol. Cleavage of the caspase-3 substrates DNA-dependent protein kinase and i nhibitor of caspase-activated deoxyribonuclease and co-localization of cyto solic caspase-3 in neurons with evidence of DNA fragmentation were also ide ntified. Intracerebral administration of the caspase-3 inhibitor N-benzylox ycarbonyl-Asp-Glu-Val-Asp-fluomethyl ketone (480 ng) after trauma reduced c aspase-3-like activity and DNA fragmentation in injured brain versus vehicl e at 24 h. Treatment with N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone for 72 h (480 ng/day) reduced contusion size and ipsilateral dorsal hippocampal tissue loss at 3 weeks but had no effect on functional outcome versus vehicle. These data demonstrate that caspase-3 activation contribute s to brain tissue loss and downstream biochemical events that execute progr ammed cell death after traumatic brain injury. Caspase inhibition may prove efficacious in the treatment of certain types of brain injury where progra mmed cell death occurs.