Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death.
Cultured mouse cortical neurons undergo apoptosis when exposed to staurosporine. The cell-permeable caspase inhibitor Z-Val-Ala-Asp fluoromethylketone (Z-VAD.FMK) attenuated this death, without altering overall protein synthesis. Z-VAD.FMK also attenuated cortical neuronal apoptosis induced by removal of serum. However, Z-VAD.FMK did not attenuate the excitotoxic necrosis induced by 5-min exposure to 100 microM NMDA, 24-h exposure to 100 microM kainate, or 90-min exposure to oxygen-glucose deprivation. We have previously shown that blockade of the excitotoxic component of oxygen-glucose deprivation-induced neuronal death with glutamate antagonists unmasks an apoptotic death. Treatment with Z-VAD.FMK, but not the cathepsin-B protease inhibitor Z-Phe-Ala fluoromethylketone (Z-FA.FMK), also attenuated this oxygen-glucose deprivation-induced neuronal apoptosis. These data support the idea that brain caspases mediate the apoptotic component of oxygen-glucose deprivation-induced neuronal death and raise the possibility that combining caspase inhibitors with glutamate antagonists might attenuate brain damage induced by hypoxic-ischemic insults in vivo.
Gottron
F J
FJ
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ying
H S
HS
Choi
D W
DW
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010100:Oxygen / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019311:Staurosporine; D005947:Glucose; D010100:Oxygen