We investigated the
neuroprotective effect of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (
AMPA)-receptor antagonist
YM90K in transient global
ischemia models. In a gerbil model, transient
ischemia was induced by bilateral common carotid artery (CCA) occlusion for 5 min. On administration at 1 hr after
ischemia, the
AMPA antagonists
NBQX (30 mg/kg, i.p. x 3) and
YM90K (15 mg/kg, i.p. x 3 or 30 mg/kg, i.p. x 3) significantly reduced the delayed neuronal death in the hippocampal CA1 region from 4 days after bilateral CCA occlusion. Furthermore,
YM90K (30 mg/kg, i.p. x 3) showed a
neuroprotective effect even when given at 6 hr after
ischemia. In contrast, the
N-methyl-D-aspartate receptor antagonists CGS19755,
MNQX (30 mg/kg, i.p. x 3, each) and (+/-)
MK-801 (10 mg/kg, i.p.) were not effective on injection at 1 hr after
ischemia in this model. In a rat model,
ischemia was induced by 4-vessel occlusion (4-VO) for 10 min.
YM90K was administered 60 min after reperfusion. Rectal and temporal muscle temperatures were maintained at the same level as in the control group for 6 hr.
YM90K markedly prevented the development of delayed neuronal death from 7 days after 4-VO at doses of 15 or 30 mg/kg, i.p. x 3, with neuroprotective efficacy similar to that in the gerbil model. These results suggest that the
AMPA receptor plays a critical role in the development of the delayed neuronal death induced by transient global
cerebral ischemia. They also suggest that the
neuroprotective effect of
YM90K is not related to its hypothermic effect.