TY - JOUR
T1 - Inhibition of interleukin-1β converting enzyme family proteases (caspases) reduces cold injury-induced brain trauma and DNA fragmentation in mice
AU - Morita-Fujimura, Yuiko
AU - Fujimura, Miki
AU - Kawase, Makoto
AU - Murakami, Kensuke
AU - Kim, Gyung Whan
AU - Chan, Pak H.
PY - 1999
Y1 - 1999
N2 - 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-1β 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.
AB - 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-1β 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.
KW - Caspase inhibitor
KW - Cold injury
KW - Neuronal apoptosis
KW - Vasogenic edema
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U2 - 10.1097/00004647-199906000-00006
DO - 10.1097/00004647-199906000-00006
M3 - Article
C2 - 10366193
AN - SCOPUS:0033238081
VL - 19
SP - 634
EP - 642
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 6
ER -