Document Detail


Delayed treatment with AMPA, but not NMDA, antagonists reduces neocortical infarction.
MedLine Citation:
PMID:  7509339     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We tested the abilities of two potent non-N-methyl-D-aspartate (non-NMDA) glutamate antagonists [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX)] and [1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazep ine hydrochloride (GYKI 52466)] to reduce neocortical infarction following 2 h of transient middle cerebral artery occlusion in a hypertensive stroke model in the rat and compared these effects against, and in combination with, a potent NMDA antagonist [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-amine maleate (MK-801)]. In Expt. 1, an already established cytoprotective dose of Na(+)-NBQX (30 mg/kg i.p. x 3) was compared with saline (1 ml), the NMDA antagonist MK-801 (1 mg/kg i.p. x 3), and a combination of the same doses of both NBQX and MK-801. Initial doses were delayed to 90 min following occlusion with subsequent injections at the time of reperfusion and 30 min following reperfusion. Saline-treated rats sustained 181 +/- 32 mm3 (n = 15) of neocortical infarction (mean +/- SD). This was significantly reduced by NBQX to 137 +/- 25 mm3 (n = 15, p < 0.05) of damage. Neither MK-801 (170 +/- 33 mm3; n = 11) nor the combination of MK-801 and NBQX (169 +/- 20 mm3; n = 6) proved to be cytoprotective when given with a 90-min delay. In Expt. 2, NBQX (30 mg/kg) was dissolved (6 mg/ml) in 5% dextrose and compared with both saline and dextrose (1.2 ml) i.v. infusions given over a 4-h period starting 1 h after occlusion. Saline-treated rats had a mean infarct of 183 +/- 27 mm3 (n = 6), dextrose-treated had 200 +/- 30 mm3 (n = 9), while for NBQX-treated rats it was reduced to 129 +/- 60 mm3 (n = 10, p < 0.05). Intravenous NBQX precipitated into the renal tubules, causing nephrotoxicity. In Expt. 3, rats were given either saline (1 ml i.p.) or GYKI 52466 (10 mg/kg i.p.) at 30 and 90 min following occlusion and at 30, 90, and 150 min following reperfusion. Saline-treated rats sustained 187 +/- 27 mm3 of neocortical infarction (n = 7), while those treated with GYKI 52466 were protected, with 139 +/- 38 mm3 of infarction (n = 7, p < 0.05). A clinically useful role for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate antagonists in embolic stroke is envisaged if nontoxic drugs can be developed, since cerebroprotection was achieved with delayed treatment with both of these lead compounds.
Authors:
D Xue; Z G Huang; K Barnes; H J Lesiuk; K E Smith; A M Buchan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  14     ISSN:  0271-678X     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  1994 Mar 
Date Detail:
Created Date:  1994-03-29     Completed Date:  1994-03-29     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:  251-61     Citation Subset:  IM    
Affiliation:
Ottawa Civic Hospital, University of Ottawa, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Anxiety Agents*
Benzodiazepines / pharmacology
Cerebral Cortex / pathology*
Cerebral Infarction / pathology*,  physiopathology
Cerebrovascular Circulation / drug effects
Injections, Intraperitoneal
Injections, Intravenous
Kidney / drug effects
Male
N-Methylaspartate / antagonists & inhibitors
Pilot Projects
Quinoxalines / pharmacology
Rats
Rats, Inbred SHR
Sodium Chloride / pharmacology
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / antagonists & inhibitors*
Chemical
Reg. No./Substance:
0/Anti-Anxiety Agents; 0/Quinoxalines; 102771-26-6/GYKI 52466; 118876-58-7/2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; 12794-10-4/Benzodiazepines; 6384-92-5/N-Methylaspartate; 7647-14-5/Sodium Chloride; 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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