Document Detail


Dependence of excitotoxic neurodegeneration on mitochondrial aconitase inactivation.
MedLine Citation:
PMID:  11520895     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Using the inactivation of mitochondrial and cytosolic aconitases as markers of compartment-specific superoxide (O2(-)) production, we show that oxygen-glucose deprivation (OGD) or excitotoxin exposure produce a time-dependent inactivation of mitochondrial, but not cytosolic, aconitase in cortical cultures. To determine if mitochondrial O2(-) production was an important determinant in neuronal death resulting from OGD, metalloporphyrins with varying superoxide dismutase (SOD) activity were tested for their ability to protect against mitochondrial aconitase inactivation and cell death. OGD-induced mitochondrial aconitase inactivation and cell death was inhibited by manganese tetrakis (4-benzoic acid) porphyrin (MnTBAP), manganese tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) and NMDA receptor antagonists. By contrast, NMDA- or kainate (KA)-induced mitochondrial aconitase inactivation and cell death was inhibited by MnTBAP, but not MnTE-2-PyP. Moreover, both MnTBAP and MnTE-2-PyP penetrated mitochondrial fractions of cortical cells. These data suggest that mitochondrial aconitase inactivation closely correlates with subsequent neuronal death following excitotoxicity produced by OGD or NMDA/KA exposure. Assessment of biological rather biochemical antioxidant activities better predicted neuroprotection by metalloporphyrins. Moreover, antioxidants that protect oxidant-sensitive mitochondrial targets such as aconitase may be useful as therapies for disease states involving excitotoxicity.
Authors:
Q Y Li; C Pedersen; B J Day; M Patel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  78     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-08-24     Completed Date:  2001-09-20     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  746-55     Citation Subset:  IM    
Affiliation:
Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
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MeSH Terms
Descriptor/Qualifier:
Aconitate Hydratase / antagonists & inhibitors,  metabolism*
Animals
Astrocytes / cytology,  drug effects,  enzymology,  metabolism
Cell Death
Cell Fractionation
Cells, Cultured
Enzyme Inhibitors / pharmacology
Fumarate Hydratase / metabolism
Glucose / metabolism
Kainic Acid / pharmacology*
Metalloporphyrins / metabolism,  pharmacology
Mitochondria / drug effects,  enzymology*
N-Methylaspartate / pharmacology*
Nerve Degeneration
Neurons / cytology,  drug effects*,  enzymology,  metabolism*
Neuroprotective Agents / pharmacology
Neurotoxins / pharmacology
Oxygen / metabolism
Paraquat / pharmacology
Rats
Superoxides / metabolism*
Grant Support
ID/Acronym/Agency:
NS39587/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Metalloporphyrins; 0/Neuroprotective Agents; 0/Neurotoxins; 11062-77-4/Superoxides; 4685-14-7/Paraquat; 487-79-6/Kainic Acid; 50-99-7/Glucose; 6384-92-5/N-Methylaspartate; 7782-44-7/Oxygen; EC 4.2.1.2/Fumarate Hydratase; EC 4.2.1.3/Aconitate Hydratase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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