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-5 H-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-5 H-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.
Delayed Treatment with AMPA, but Not NMDA, Antagonists Reduces Neocortical Infarction