Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation.
Caspase-3 is a major cell death effector protease in the adult and neonatal nervous system. We found a greater number and higher density of cells in the cortex of caspase-3(-/-) adult mice, consistent with a defect in developmental cell death. Caspase-3(-/-) mice were also more resistant to ischemic stress both in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical infarct volume was reduced by 55%, and the density of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells was decreased by 36% compared with wild type. When subjected to oxygen-glucose deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3 expression were also more resistant to cell death by 59%. Mutant brains showed caspase-specific poly(ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase-mediated cell death. In the present study, we found that caspase-8 mediated poly(ADP-ribose) polymerase cleavage in caspase-3(-/-) neurons in vivo and in vitro. In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the pharmacological evidence supporting an important role for caspase-3 and caspase-8 as cell death mediators in mammalian cortex and indicate the potential advantages of targeting more than a single caspase family member to treat ischemic cell injury.
Le
Dean A
DA
Stroke and Neurovascular Regulation Laboratory, Boston, MA 02114, USA.
Wu
Yongqin
Y
Huang
Zhihong
Z
Matsushita
Kohji
K
Plesnila
Nikolaus
N
Augustinack
Jean C
JC
Hyman
Bradley T
BT
Yuan
Junying
J
Kuida
Keisuke
K
Flavell
Richard A
RA
Moskowitz
Michael A
MA
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency* / Q000378:metabolism*; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D020768:Middle Cerebral Artery; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology; D010100:Oxygen / Q000097:blood; D010641:Phenotype; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015424:Reperfusion
D011065:Poly(ADP-ribose) Polymerases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005947:Glucose; D010100:Oxygen