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 damage defining apoptosis. The participation of caspase-3 activation in the evolution of neuronal death after traumatic brain injury in rats was examined. Cleavage of pro-caspase-3 in cytosolic cellular fractions and an increase in caspase-3-like enzyme activity were seen in injured brain versus control. Cleavage of the caspase-3 substrates DNA-dependent protein kinase and inhibitor of caspase-activated deoxyribonuclease and co-localization of cytosolic caspase-3 in neurons with evidence of DNA fragmentation were also identified. Intracerebral administration of the caspase-3 inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (480 ng) after trauma reduced caspase-3-like activity and DNA fragmentation in injured brain versus vehicle 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 contributes to brain tissue loss and downstream biochemical events that execute programmed cell death after traumatic brain injury. Caspase inhibition may prove efficacious in the treatment of certain types of brain injury where programmed cell death occurs.
Clark
R S
RS
Department of Anesthesiology and Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pennsylvania 15260, USA. clark@smtp.anes.upmc.edu
Kochanek
P M
PM
Watkins
S C
SC
Chen
M
M
Dixon
C E
CE
Seidberg
N A
NA
Melick
J
J
Loeffert
J E
JE
Nathaniel
P D
PD
Jin
K L
KL
Graham
S H
SH
D000818:Animals; D015415:Biomarkers; D001930:Brain Injuries / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats
D015415:Biomarkers; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases