Document Detail


Characterization of neuroprotection from excitotoxicity by moderate and profound hypothermia in cultured cortical neurons unmasks a temperature-insensitive component of glutamate neurotoxicity.
MedLine Citation:
PMID:  9701346     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although profound hypothermia has been used for decades to protect the human brain from hypoxic or ischemic insults, little is known about the underlying mechanism. We therefore report the first characterization of the effects of moderate (30 degrees C) and profound hypothermia (12 degrees to 20 degrees C) on excitotoxicity in cultured cortical neurons exposed to excitatory amino acids (EAA; glutamate, N-methyl-D-aspartate [NMDA], AMPA, or kainate) at different temperatures (12 degrees to 37 degrees C). Cooling neurons to 30 degrees C and 20 degrees C was neuroprotective, but cooling to 12 degrees C was toxic. The extent of protection depended on the temperature, the EAA receptor agonist employed, and the duration of the EAA challenge. Neurons challenged briefly (5 minutes) with all EAA were protected, as were neurons challenged for 60 minutes with NMDA, AMPA, or kainate. The protective effects of hypothermia (20 degrees and 30 degrees C) persisted after rewarming to 37 degrees C, but rewarming from 12 degrees C was deleterious. Surprisingly, however, prolonged (60 minutes) exposures to glutamate unmasked a temperature-insensitive component of glutamate neurotoxicity that was not seen with the other, synthetic EAA; this component was still mediated via NMDA receptors, not by ionotropic or metabotropic non-NMDA receptors. The temperature-insensitivity of glutamate toxicity was not explained by effects of hypothermia on EAA-evoked [Ca2+]i increases measured using high- and low-affinity Ca2+ indicators, nor by effects on mitochondrial production of reactive oxygen species. This first characterization of excitotoxicity at profoundly hypothermic temperatures reveals a previously unnoticed feature of glutamate neurotoxicity unseen with the other EAA, and also suggests that hypothermia protects the brain at the level of neurons by blocking, rather than slowing, excitotoxicity.
Authors:
M Tymianski; R Sattler; J M Zabramski; R F Spetzler
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  18     ISSN:  0271-678X     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  1998 Aug 
Date Detail:
Created Date:  1998-08-21     Completed Date:  1998-08-21     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  848-67     Citation Subset:  IM    
Affiliation:
The Toronto Hospital Research Institute, and Division of Neurosurgery, The Toronto Hospital, University of Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism
Cell Survival / drug effects,  physiology
Cells, Cultured
Cerebral Cortex / cytology,  physiology*
Cold Temperature
Cycloleucine / analogs & derivatives,  toxicity
Embryo, Mammalian
Excitatory Amino Acid Antagonists / pharmacology*
Excitatory Amino Acids / toxicity*
Fluorescent Dyes
Glutamic Acid / toxicity
Humans
Hypothermia, Induced*
Kainic Acid / toxicity
Mice
N-Methylaspartate / toxicity
Neuroglia / cytology*,  drug effects,  pathology
Neurons / cytology*,  drug effects,  pathology
Neurotoxins / toxicity*
Synapses / drug effects,  physiology
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / toxicity
Chemical
Reg. No./Substance:
0/Excitatory Amino Acid Antagonists; 0/Excitatory Amino Acids; 0/Fluorescent Dyes; 0/Neurotoxins; 111900-32-4/1-amino-1,3-dicarboxycyclopentane; 487-79-6/Kainic Acid; 52-52-8/Cycloleucine; 56-86-0/Glutamic Acid; 6384-92-5/N-Methylaspartate; 7440-70-2/Calcium; 77521-29-0/alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

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


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