dizocilpine-maleate and efaproxiral

In a recent study of focal cerebral ischemia in rats, pre-ischemic administration of the synthetic allosteric hemoglobin modifier RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl] methyl] phenoxy]-2-methylproprionic acid) reduced cerebral infarct size when combined with the NMDA receptor antagonist dizocilpine (MK-801) but not when given alone. We hypothesized that post-ischemic RSR13 administration would enhance neuroprotection afforded by NMDA receptor antagonism in a rat model of transient middle cerebral artery occlusion (MCAO). Fasted normothermic Wistar rats underwent 75 min of temporary MCAO. At onset of reperfusion, rats randomly received: (1) 0.9% NaCl (vehicle) i.v. alone (n=16); (2) 0.9% NaCl+dizocilpine (0.25 mg/kg) i.v. (n=16); or (3) RSR13 (150 mg/kg)+dizocilpine (0.25 mg/kg) i.v. (n=17). Seven days later, neurologic deficit and cerebral infarct size were determined. Dizocilpine alone compared to vehicle reduced mean+/-S.D. subcortical (52+/-24 mm(3) vs. 122+/-64 mm(3), P=0.003) and cortical (35+/-35 mm(3) vs. 125+/-72 mm(3), P=0.00074) infarct volumes. When compared to dizocilpine alone, the combination of RSR13+dizocilpine further reduced subcortical (37+/-14 mm(3) vs. 52+/-24 mm(3), P=0. 034) and cortical (8+/-19 mm(3) vs. 35+/-35 mm(3), P=0.018) infarct size. RSR13+dizocilpine improved neurologic scores vs. either dizocilpine alone (P=0.0014) or vehicle (P=10(-7)). The combination of NMDA receptor antagonism and a RSR13 mediated rightward shift of the oxy-hemoglobin dissociation curve improved outcome from MCAO. Because this occurred after reperfusion, our results suggest that the post-ischemic brain continues to suffer from hypoperfusion defects, which are amenable to therapy by enhanced O(2) delivery. The results also support the concept that neuroprotective strategies, which combine drugs with different mechanisms of action, may yield cumulative benefits.

Topics: Aniline Compounds; Animals; Blood Gas Analysis; Body Temperature; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Hemoglobins; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Neurologic Examination; Neuroprotective Agents; Propionates; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

This study examined the effect of a pharmacologically induced rightward shift in the partial pressure of oxygen at which 50% of hemoglobin is saturated (P50) on outcome from transient focal cerebral ischemia in the rat. Halothane 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]methyl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after onset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven days 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 intravenously and subjected to 75 min of MCAO with 7 days of recovery. Again, RSR13 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 MCAO 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 resulted in smaller cortical infarct volume (8+/-14 mm3 vs. 34+/-37 mm3, p<0.02) and total cerebral infarct volume (46+/-28 mm3 vs. 81+/-60 mm3, p<0. 05) compared to dizocilpine alone, respectively. We conclude that a pre-ischemic peak increase in P50 of approximately 25 mmHg alone is insufficient to reduce focal ischemic injury, but may be advantageous when used in conjunction with other neuroprotective agents.

Topics: Allosteric Site; Aniline Compounds; Animals; Antisickling Agents; Blood Gas Analysis; Body Temperature; Brain Chemistry; Cerebral Cortex; Cerebral Infarction; Dizocilpine Maleate; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Hemoglobins; Ischemic Attack, Transient; Male; Propionates; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate