Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.
Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatized brain tissue. Reduction of tissue injury and free radical production following brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also conferred by pharmacological inhibition of caspase-1 by intracerebroventricular administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone or the non-selective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces trauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1beta converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.
Fink
K B
KB
Stroke and Neurovascular Regulation, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Andrews
L J
LJ
Butler
W E
WE
Ona
V O
VO
Li
M
M
Bogdanov
M
M
Endres
M
M
Khan
S Q
SQ
Namura
S
S
Stieg
P E
PE
Beal
M F
MF
Moskowitz
M A
MA
Yuan
J
J
Friedlander
R M
RM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000235:genetics / Q000473:pathology*; D020170:Caspase 1 / Q000502:physiology; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D017665:Hydroxyl Radical / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D017665:Hydroxyl Radical; D020170:Caspase 1