SM-31900, a novel NMDA receptor glycine-binding site antagonist, reduces infarct volume induced by permanent middle cerebral artery occlusion in spontaneously hypertensive rats
| Autor: | Yukihiro Ohno, Hiroyasu Tanaka, Ken-ichi Ohtani |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
Middle Cerebral Artery Indoles Ischemia Pharmacology Receptors N-Methyl-D-Aspartate Rats Sprague-Dawley Brain ischemia Cellular and Molecular Neuroscience Receptors Glycine Bolus (medicine) Glycine binding Species Specificity Rats Inbred SHR medicine.artery medicine Animals cardiovascular diseases Rats Wistar Ligation Dose-Response Relationship Drug business.industry Antagonist Infarction Middle Cerebral Artery Cell Biology medicine.disease Rats Dose–response relationship Neuroprotective Agents Anesthesia Middle cerebral artery NMDA receptor business |
| Zdroj: | Neurochemistry International. 42:375-384 |
| ISSN: | 0197-0186 |
| DOI: | 10.1016/s0197-0186(02)00137-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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