NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus

Recent studies have shown that a brief 'pre-conditioning' ischaemic insult reduces the hippocampal cell death caused by a subsequent more severe test insult. In the present studies, we have examined the effects of the non-com petitive NMDA receptor antagonist ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-d ibenzo[a,d]cyclohepten-5,10-imine, MK-801) a competitive NMDA receptor anta gonist, LY202157, AMPA receptor antagonist ((3S,4aR,6R,8aR)-6-[2-(1(2)H-tet razole-5-yl)]decahydroisoquinoline-3-carboxylic acid, LY293558), a non-comp etitive AMPA receptor antagonist ((-)-1-(4-amino-phenyl)-4-methyl-7,8-methy lenedioxy-4,5-dihydro-3-acetyl-2,3-benzodiazepine, LY300164), and a mixed N MDA/AMPA receptor antagonist, LY246492, in a gerbil model of ischaemic tole rance. Ischaemic tolerance was induced by subjecting gerbils to a 2-min 'pr e-conditioning' ischaemia (bilateral carotid occlusion)2 days prior to a 3- min test ischaemia. The effects of MK-801 (2 mg/kg i.p.), LY293558 (20 mg/k g i.p., followed by 4 x 10 mg/kg at 3 h intervals), LY300164 (4 x 10 mg/kg i.p. at 1 h intervals), LY246492 (40 mg/kg i.p., followed by 4 x 20 mg/kg i .p. at 3 h intervals) and LY202157 (30 mg/kg i.p., followed by 4 x 15 mg/kg i.p. at 2 h intervals) were then examined in this model. Initial dosing co mmenced 30 min prior to the 2-min 'pre-conditioning' ischaemia. Results ind icated that a 2-min 'pre-conditioning' ischaemia produced ischaemic toleran ce in all cases. The non-competitive NMDA receptor antagonist, MK-801, prod uced a significant (P < 0.01) reduction in the induced tolerance, while the competitive NMDA receptor antagonist, LY202157, also attenuated(P < 0.05) the induction of tolerance. In contrast, two AMPA receptor antagonists (LY2 93558 and:LY300164) and a mixed NMDA/AMPA receptor antagonist (LY246492) ha d no effect on the induction of tolerance. These results suggest that NMDA receptor activation, but not AMPA receptor activation is involved in the ph enomenon of ischaemic tolerance. (C) 1999 Elsevier Science B.V. All rights reserved.