Document Detail


Pharmacological modification of glutamate neurotoxicity in vivo.
MedLine Citation:
PMID:  7506985     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The ability of five agents (dizocilpine [MK-801], 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline [NBQX], enadoline [CI-977], L-nitroarginine methyl ester [L-NAME] and BW 1003c87) with well defined, distinct pharmacological profiles and with established anti-ischemic efficacy, to modify neuronal damage has been examined in a simple in vivo model of glutamate excitotoxicity. Cortical lesions were produced in physiologically-monitored halothane-anesthetised rats by reverse dialysis of glutamate. The volume of the lesion was quantified histologically by image analysis of approximately 20 sections taken at 200 microm intervals throughout the lesion. The AMPA and NMDA receptor antagonists (NBQX and MK-801) and the inhibitor of nitric oxide synthase (L-NAME) significantly reduced the lesion volume by a similar extent (by approximately 30% from vehicle). Two agents (the kappa opioid agonist, CI-977 and the sodium channel blocker, BW 1003c87) which putatively inhibit the release of endogenous glutamate presynaptically, had dissimilar effects on lesion size. CI-977 failed to alter the amount of damage produced by exogenous glutamate, whereas BW 1003c87 reduced the lesion size by approximately 50%. Using this model, the neuroprotective effects of anti-ischemic drugs can be explored in vivo, uncomplicated in contrast to experimental ischemia by reduced oxygen delivery, drug effects on tissue blood flow and compromised energy generation. In consequence, additional mechanistic insight into anti-ischemic drug action in vivo can be obtained.
Authors:
H Fujisawa; D Dawson; S E Browne; K B MacKay; R Bullock; J McCulloch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Brain research     Volume:  629     ISSN:  0006-8993     ISO Abbreviation:  Brain Res.     Publication Date:  1993 Nov 
Date Detail:
Created Date:  1994-02-23     Completed Date:  1994-02-23     Revised Date:  2009-09-29    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  73-8     Citation Subset:  IM    
Affiliation:
Wellcome Neuroscience Group, University of Glasgow, Scotland, UK.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Oxidoreductases / antagonists & inhibitors
Animals
Arginine / analogs & derivatives,  pharmacology
Benzofurans / pharmacology
Blood Pressure / drug effects*
Brain Ischemia / prevention & control
Cerebral Cortex / drug effects,  metabolism,  pathology*
Dizocilpine Maleate / pharmacology
Glutamates / antagonists & inhibitors*,  toxicity*
Glutamic Acid
Male
Microdialysis
NG-Nitroarginine Methyl Ester
Neurons / drug effects,  metabolism,  pathology*
Neurotoxins / antagonists & inhibitors,  toxicity*
Nitric Oxide Synthase
Pyrimidines / pharmacology
Pyrrolidines / pharmacology
Quinoxalines / pharmacology
Rats
Rats, Sprague-Dawley
Time Factors
Grant Support
ID/Acronym/Agency:
//Wellcome Trust
Chemical
Reg. No./Substance:
0/Benzofurans; 0/Glutamates; 0/Neurotoxins; 0/Pyrimidines; 0/Pyrrolidines; 0/Quinoxalines; 107431-28-7/enadoline; 118876-58-7/2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; 144425-86-5/5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine ethane sulfonate; 50903-99-6/NG-Nitroarginine Methyl Ester; 56-86-0/Glutamic Acid; 74-79-3/Arginine; 77086-22-7/Dizocilpine Maleate; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.4.-/Amino Acid Oxidoreductases

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