SM-31900, a novel NMDA receptor glycine-binding site antagonist, reduces infarct volume induced by permanent middle cerebral artery occlusion in spontaneously hypertensive rats.
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.
Ohtani
Ken-ichi
K
Research Center, Sumitomo Pharmaceuticals Co. Ltd., 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan. ohtani@sumitomopharm.co.jp
Tanaka
Hiroyasu
H
Ohno
Yukihiro
Y
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology* / Q000517:prevention & control*; D008026:Ligation; D008297:Male; D020768:Middle Cerebral Artery / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013045:Species Specificity
D007211:Indoles; D018696:Neuroprotective Agents; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C466317:SM 31900