Administration of a competitive NMDA antagonist MDL-100,453 reduces infarct size after permanent middle cerebral artery occlusion in rat.

Abstract

The competitive N-methyl-D-aspartate antagonist MDL-100,453 has been shown to attenuate ischemic cell damage when administered after permanent focal cerebral ischemia. The aim of the present study was to measure the dose-response of cerebral infarcted volume to the agent administered 30 min after permanent middle cerebral artery occlusion and to test whether short-term infusion of this drug reduces ischemic cell damage. Thirty-five Sprague-Dawley rats were randomly assigned to 4 groups: low dose group, a bolus of 12.4 mg/kg MDL-100,453 followed by infusion of 31.7 mg/kg/h MDL-100,453; middle and high dose groups, bolus and infusion doses increased to 24.8 mg/kg, 63.3 mg/kg/h and 49.6 mg/kg, 126.7 mg/kg/h, respectively; and control group, saline used for bolus and infusion. Middle cerebral artery occlusion (MCAO) was induced by insertion of intraluminal suture. The infusion was accomplished by a microprocessor controlled pump connected to a jugular vein, which delivered drug or saline over a period of 9 h. Infarct volume was calculated using 2,3,5-triphenyltetrazolium chloride staining 24 h after MCAO. The infarct volumes were significantly reduced in both middle (46%) and high (52%) dose groups compared with the saline group (p < 0.05). No reduction of infarct volume was found in the low dose group. A statistically significant (p < 0.05), but poor inverse correlation existed between the average blood level of MDL-100,453 and infarct volume. We demonstrated that a short-term (9 h) intravenous administration of an appropriate dose of MDL-100,453 beginning 30 min after MCAO significantly reduces ischemic lesion volume at 24 h after onset of permanent focal cerebral ischemia.

• Authors: N Jiang, R L Zhang, B M Baron, M Chopp
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 138 Issue 1-2 Pg. 36-41 (Jun 1996) ISSN: 0022-510X [Print] Netherlands
• PMID: 8791236 (Publication Type: Journal Article)

Chemical References

• Excitatory Amino Acid Antagonists
• Receptors, N-Methyl-D-Aspartate
• 4-oxo-5-phosphononorvaline
• Valine

Topics

• Animals
• Arterial Occlusive Diseases (drug therapy)
• Brain Ischemia (drug therapy)
• Cerebral Arteries
• Cerebral Infarction (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Excitatory Amino Acid Antagonists (pharmacology)
• Infusions, Intravenous
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Valine (analogs & derivatives, pharmacology)