Objective: The use of competitive and noncompetitive N-methyl-D-aspartate receptor antagonists to prevent neuronal death during ischemia has been comprehensively studied. This study was performed to examine the neuroprotective effects and pharmacokinetics of the noncompetitive N-methyl-D-aspartate receptor 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 cerebral ischemia was induced in 21 cats. After 30 minutes of a 90-min ischemic insult, 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 was positioned for both T2- and diffusion-weighted scans (eight slices, 5-mm thick). At 8 hours after ischemia, the animals were perfusion-fixed for histopathological analysis.
Results: Pharmacokinetic studies indicated that AR-R15896AR remained in the blood at elevated levels for the 6 hours studied, with a calculated half-life of approximately 6 hours. AR-R15896AR rapidly entered the brain and exhibited a brain/plasma ratio of approximately 8:1. The infarction volumes for the AR-R15896AR-treated group were 1138.5+/-363.1, 651.3+/-428.9, and 118.6+/-50.1 mm3, as calculated using diffusion- and T2-weighted MRI and histopathological data, respectively. The infarction volumes for the control group were 3866.3+/-921, 3536+/-995.7, and 359.9+/-80.2 mm3, as calculated using diffusion- and T2-weighted MRI and histopathological data, respectively. No significant changes were observed in the physiological parameters measured (mean arterial blood pressure, pH, arterial carbon dioxide pressure, arterial oxygen pressure, sodium, potassium, chloride, and glucose levels, hematocrit, and temperature) for either the control or AR-R15896AR-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 histopathological 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 scans exibiting the largest infarction volumes.