AR-R15896AR, a low affinity, use-dependent, NMDA antagonist, is protective in a primate model of stroke

• Published in: Journal of stroke and cerebrovascular diseases 2000-11, Vol.9 (6), p.303-312
• Main Authors: Marshall, Jonathan W.B., Jones, Ellen J., Duffin, Katherine J., Curry, Stephen H., Ridley, Rosalind M.
• Format: Article
• Language: English
• Subjects: Monkeys; Neglect; NMDA antagonist
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1053/jscd.2000.18738

The low affinity, use-dependent, N-methyl- D-aspartate (NMDA) antagonist, AR-R15896AR, is neuroprotective against transient focal cerebral ischemia in rats. We have examined the effect of AR-R15896AR, administered at a plasma level that is tolerated in acute stroke patients, on both functional and histopathologic measures in marmoset monkeys with permanent middle cerebral artery (MCA) occlusion. The M1 segment of the right MCA was permanently occluded (pMCAO) by bipolar coagulation in 11 marmosets. Five minutes later, the monkeys received either saline or AR-R15896 (4.5 mg/kg) intravenously, infused over 30 seconds. Also, osmotic minipumps were implanted subcutaneously to provide continuous drug or saline infusion for 48 hours. Drug-filled pumps released AR-R15896 at a rate of 1.1 mg/kg/h. The monkeys had been trained and tested preoperatively on a number of behavioral tasks and were retested 3 and 10 weeks after surgery. Three weeks after surgery, all the monkeys had a severe motor deficit, in that they were impaired at reaching with their contralesional arms, and perceptual neglect of contralesional space. AR-R15896AR-treated monkeys, however, had significantly less neglect than saline-treated monkeys, although the AR-R15896AR treatment had no effect on the motor deficit. By 10 weeks, the neglect had recovered, but not the motor deficit, and there were no differences between the 2 groups. Histopathologic analysis showed a reduction in the size of the infarction at several stereotaxic levels of the AR-R15896AR-treated monkeys. This study has shown that AR-R15896AR protected a select region of the brain against permanent focal cerebral ischemia in a primate species and attenuated the ensuing spatial neglect.