Document Detail

Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation.
MedLine Citation:
PMID:  12415117     Owner:  NLM     Status:  MEDLINE    
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.
Dean A Le; Yongqin Wu; Zhihong Huang; Kohji Matsushita; Nikolaus Plesnila; Jean C Augustinack; Bradley T Hyman; Junying Yuan; Keisuke Kuida; Richard A Flavell; Michael A Moskowitz
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2002-11-01
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  99     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-11-13     Completed Date:  2003-01-15     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15188-93     Citation Subset:  IM    
Stroke and Neurovascular Regulation Laboratory, Boston, MA 02114, USA.
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MeSH Terms
Caspase 3
Caspases / deficiency*,  metabolism*
Cells, Cultured
Cerebral Infarction / pathology,  physiopathology*
Disease Models, Animal
Enzyme Activation
Glucose / metabolism*
In Situ Nick-End Labeling
Ischemic Attack, Transient / physiopathology*
Mice, Knockout
Middle Cerebral Artery
Models, Neurological
Neurons / physiology
Oxygen / blood
Poly(ADP-ribose) Polymerases / metabolism
Grant Support
Reg. No./Substance:
50-99-7/Glucose; 7782-44-7/Oxygen; EC Polymerases; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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