Effects of RSR13, a synthetic allosteric modifier of hemoglobin, alone andin combination with dizocilpine, on outcome from transient focal cerebral ischemia in the rat

This study examined the effect of a pharmacologically induced rightward shi ft in the partial pressure of oxygen at which 50% of hemoglobin is saturate d (P-50) on outcome from transient focal cerebral ischemia in the rat, Halo thane anesthetized rats (n = 20 per group) were given saline or a single 15 -min infusion of 150 mg/kg RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl]meth yl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after o nset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven d ays later, severity of hemiparesis and cerebral infarct size were examined. RSR13 alone did not significantly improve outcome. Conscious normothermic rats (n = 12 per group) were also given RSR13 (150 mg/kg) or 0.9% NaCl intr avenously and subjected to 75 min of MCAO with 7 days of recovery. Again, R SR13 alone did not significantly reduce infarct size or improve neurologic score. A dose-response curve for dizocilpine (MK-801) was then constructed in conscious normothermic rats subjected to 75 min of MCAO, Dizocilpine (0. 5 mg/kg i.v.) caused a 90% reduction in mean infarct size while 0.25 mg/kg reduced infarct size by 48%, Other rats were then subjected to 75 min of MC AO after being given dizocilpine (0.25 mg/kg i.v.; n = 18) or RSR13 (150 mg /kg i.v.) + dizocilpine (0.25 mg/kg i.v.; n = 15). RSR13 + dizocilpine resu lted in smaller cortical infarct volume (8 +/- 14 mm(3) vs, 34 +/- 37 mm(3) , p < 0.02) and total cerebral infarct volume (46 +/- 28 mm3 vs. 81 +/- 60 mm(3), p < 0.05) compared to dizocilpine alone, respectively, We conclude t hat a pre-ischemic peak increase in P-50 of similar to 25 mmHg alone is ins ufficient to reduce focal ischemic injury, but may be advantageous when use d in conjunction with other neuroprotective agents. (C) 1999 Elsevier Scien ce B.V. All rights reserved.