| Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. | |
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MedLine Citation:
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PMID: 12415117 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2002-11-01 |
Journal Detail:
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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:
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Created Date: 2002-11-13 Completed Date: 2003-01-15 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 15188-93 Citation Subset: IM |
Affiliation:
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Stroke and Neurovascular Regulation Laboratory, Boston, MA 02114, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis 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 Mice, Knockout Middle Cerebral Artery Models, Neurological Neurons / physiology Oxygen / blood Phenotype Poly(ADP-ribose) Polymerases / metabolism Reperfusion |
| Grant Support | |
ID/Acronym/Agency:
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1 R01 NS374141/NS/NINDS NIH HHS; K08 NS02162/NS/NINDS NIH HHS; NS 5 P50 NS 10828/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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50-99-7/Glucose; 7782-44-7/Oxygen; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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