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SM-31900, a novel NMDA receptor glycine-binding site antagonist, reduces infarct volume induced by permanent middle cerebral artery occlusion in spontaneously hypertensive rats.

Abstract
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.
AuthorsKen-ichi Ohtani, Hiroyasu Tanaka, Yukihiro Ohno
JournalNeurochemistry international (Neurochem Int) Vol. 42 Issue 5 Pg. 375-84 (Apr 2003) ISSN: 0197-0186 [Print] England
PMID12510020 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Indoles
  • Neuroprotective Agents
  • Receptors, Glycine
  • Receptors, N-Methyl-D-Aspartate
  • SM 31900
Topics
  • Animals
  • Dose-Response Relationship, Drug
  • Indoles (pharmacology)
  • Infarction, Middle Cerebral Artery (pathology, prevention & control)
  • Ligation
  • Male
  • Middle Cerebral Artery (pathology)
  • Neuroprotective Agents (pharmacology)
  • Rats
  • Rats, Inbred SHR
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Glycine (antagonists & inhibitors)
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
  • Species Specificity

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