Sachiko Kawasaki-Yatsugi, Shin-ichi Yatsugi, Kazuo Koshiya and Masao
Shimizu-Sasamata
Neuroscience Research, Pharmacological Laboratory, Institute for Drug
Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka,
Tsukuba, Ibaraki 305, Japan
Abstract: 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.
Keywords: AMPA receptor, Global cerebral ischemia, Delayed neuronal death