AR-R15896AR reduces cerebral infarction volumes after focal ischemia in cats

OBJECTIVE: The use of competitive and noncompetitive N-methyl-D-aspartate r eceptor antagonists to prevent neuronal death during ischemia has been comp rehensively studied. This study was performed to examine the neuroprotectiv e effects and pharmacokinetics of the noncompetitive N-methyl-D-aspartate r eceptor channel blocker (S)-alpha-phenylpyridine-ethanamine dihydrochloride , AR-R15896AR (formerly designated ARL 15896AR), using a gyrencephalic cat middle cerebral artery occlusion model. METHODS: In a separate experiment, three cats were used for pharmacokinetic analysis, thus establishing the optimal dose of AR-R15896AR. Focal cerebra l ischemia was induced in 21 cats. After 30 minutes of a 90-min ischemic in sult, the cats received an intravenous infusion (total volume, 3 ml), in a 15-minute period, of either AR-R15896AR or normal saline solution (control) . Physiological data were obtained after 40 and 80 minutes of ischemia and at 2, 4, and 6 hours after ischemia. At 6 hours after ischemia, each cat wa s positioned for both T2- and diffusion-weighted scans (eight slices, 5-mm thick). At 8 hours after ischemia, the animals were perfusion-fixed for his topathological analysis. RESULTS: Pharmacokinetic studies indicated that AR-R15896AR remained in the blood at elevated levels for the 6 hours studied, with a calculated half-l ife of approximately 6 hours. AR-R15896AR rapidly entered the brain and exh ibited a brain/plasma ratio of approximately 8:1. The infarction volumes fo r the AR-R15896AR-treated group were 1138.5 +/- 363.1, 651.3 +/- 428.9, and 118.6 +/- 50.1 mm(3), as calculated using diffusion- and T2-weighted MRI a nd histopathological data, respectively. The infarction volumes for the con trol group were 3866.3 +/- 921, 3536 +/- 995.7, and 359.9 +/- 80.2 mm(3), a s calculated using diffusion- and T2-weighted MRI and histopathological dat a, respectively. No significant changes were observed in the physiological parameters measured (mean arterial blood pressure, pH, arterial carbon diox ide pressure, arterial oxygen pressure, sodium, potassium, chloride, and gl ucose levels, hematocrit, and temperature) for either the control or AR-R15 896AR-treated group. Postischemic calcium levels returned to normal in the AR-R15896AR-treated cats, whereas they decreased in the control cats. CONCLUSION: When administered after ischemia, AR-R15896AR was effective in significantly reducing infarction volumes, as measured using diffusion- or T2-weighted magnetic resonance imaging data or quantitative histopathologic al data. This study also demonstrated that infarction volumes were greater in the diffusion- and T2-weighted magnetic resonance imaging scans than in the qualitative histopathological analyses, with the diffusion-weighted sca ns exhibiting the largest infarction volumes.