Delayed Treatment with AMPA, but Not NMDA, Antagonists Reduces Neocortical Infarction

• Published in: Journal of cerebral blood flow and metabolism 1994-03, Vol.14 (2), p.251-261
• Main Authors: Xue, Dong, Huang, Zhi-Gao, Barnes, Kimberley, Lesiuk, Howard J., Smith, Karen E., Buchan, Alastair M.
• Format: Article
• Language: English
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - antagonists & inhibitors; Animals; Anti-Anxiety Agents; Benzodiazepines - pharmacology; Biological and medical sciences; Cerebral Cortex - pathology; Cerebral Infarction - pathology; Cerebral Infarction - physiopathology; Cerebrovascular Circulation - drug effects; Injections, Intraperitoneal; Injections, Intravenous; Kidney - drug effects; Male; Medical sciences; N-Methylaspartate - antagonists & inhibitors; Neurology; Pilot Projects; Quinoxalines - pharmacology; Rats; Rats, Inbred SHR; Sodium Chloride - pharmacology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.1994.32

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-benzodiazepine 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. × 3) was compared with saline (1 ml), the NMDA antagonist MK-801 (1 mg/kg i.p. × 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 α-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.