Inhibition of interleukin-1beta converting enzyme family proteases (caspases) reduces cold injury-induced brain trauma and DNA fragmentation in mice.
The authors examined the effect of z-VAD.FMK, an inhibitor that blocks caspase family proteases, on cold injury-induced brain trauma, in which apoptosis as well as necrosis is assumed to play a role. A vehicle alone or with z-VAD.FMK was administered into the cerebral ventricles of mice 15 minutes before and 24 and 48 hours after cold injury. At 24 hours after cold injury, infarction volumes in the z-VAD.FMK-treated animals were significantly smaller than infarction volumes in the vehicle-treated animals, and were further decreased at 72 hours (0.92 +/- 1.80 mm3, z-VAD.FMK-treated animals; 7.46 +/- 3.53 mm3, vehicle-treated animals; mean +/- SD, n = 7 to 8). The amount of DNA fragmentation was significantly decreased in the z-VAD.FMK-treated animals compared with the vehicle-treated animals, as shown by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling staining and DNA gel electrophoresis. By Western blot analysis, both the proform and activated form of interleukin-1beta converting enzyme (caspase 1) were detected in the control brain, and the activated form showed moderate reduction after cold injury-induced brain trauma. These results indicate that caspase inhibitors could reduce cold injury-induced brain trauma by preventing neuronal cell death by DNA damage. The caspase family proteases appear to contribute to the mechanisms of cell death in cold injury-induced brain trauma and to provide therapeutic targets for traumatic brain injury.
Morita-Fujimura
Y
Y
Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California 94304, USA.
Fujimura
M
M
Kawase
M
M
Murakami
K
K
Kim
G W
GW
Chan
P H
PH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D061945:Caspase Inhibitors; D003080:Cold Temperature / Q000009:adverse effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone