The purpose of this study was to investigate the effect of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]
indole-2-
carboxylic acid hydrochloride (SM-31900), an antagonist with high selectivity and affinity for the
NMDA receptor glycine-binding site, on the
cerebral infarct volume in a permanent
middle cerebral artery occlusion (MCAo) model, which was constructed by
electrocoagulation of a unilateral middle cerebral artery distal to the olfactory tract using spontaneously hypertensive rats (SHRs). To investigate the dose-response characteristics and the therapeutic time window of
SM-31900 in this MCAo model, we conducted three experiments, in which the administration of
SM-31900 was started 5min (experiment I), 30min (experiment II), or 60min (experiment III) after MCAo, respectively. In all the studies,
SM-31900 was administered by intravenous bolus injection followed by continuous
intravenous infusion to obtain a steady-state level of this compound in blood immediately after its administration. The treatment with
SM-31900 was continued until 24h after MCAo, at which time the
cerebral infarct volume was measured. In experiment I,
SM-31900 significantly reduced the
infarct volume by 37% at a dosage of 0.38mg/kg bolus followed by 1.5mg/kg/h continuous infusion (0.38mg/kg+1.5mg/kg/h). In experiment II, the
neuroprotective effect of
SM-31900 was also significant, with a 25% reduction in
infarct volume at a dosage of 0.38mg/kg+1.5mg/kg/h, and a 40% reduction at 1.5mg/kg+6.0mg/kg/h. Furthermore, even in experiment III,
SM-31900 exerted a significant
neuroprotective effect, with a 20% reduction at 1.5mg/kg+6.0mg/kg/h. These studies revealed that
SM-31900 can exert a
neuroprotective effect when it is administered up to at least 60min after the onset of
ischemia in the MCAo model, an animal model of
stroke, indicating that
SM-31900 is a good candidate for treating acute
brain ischemia.