Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat

In a recent study of focal cerebral ischemia in rats, pre-ischemic administ ration of the synthetic allosteric hemoglobin modifier RSR13 (2-[4-[[3,5 -d imethylanilino carbonyl] methyl] phenoxy]-2-methylproprionic acid) reduced cerebral infarct size when combined with the NMDA receptor antagonist dizoc ilpine (MK-801) but not when given alone. We hypothesized that post-ischemi c RSR13 administration would enhance neuroprotection afforded by NMDA recep tor 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. (II = 17), Seve n days later, neurologic deficit and cerebral infarct size were determined. Dizocilpine alone,compared to vehicle reduced mean +/- S.D. subcortical (5 2 +/- 21 mm(3)) vs. 122 +/- 64 mm(3) P = 0.003 and cortical (35 +/- 35 mm(3 ) vs. 125 1 72 mm(3), P = 0.00074) infarct volumes. When compared to dizoci lpine alone, the combination of RSR13 + dizocilpine further reduced subcort ical (37 +/- 14 mm(3) vs. 52 +/- 24 mm3, P = 0.034) and cortical (8 +/- 19 mm3 vs, 35 +/- 35 mm3, P = 0.018) infarct size. RSR13 + dizocilpine improve d neurologic scores vs. either dizocilpine alone (P = 0.0014) or vehicle (P = 10(-7)). The combination of NMDA receptor antagonism and a RSR13 mediate d rightward shift of the oxy-hemoglobin dissociation curve improved outcome from MCAO. Because this occurred after reperfusion, our results suggest th at the post-ischemic brain continues to suffer from hypoperfusion defects, which are amenable to therapy by enhanced O-2, delivery. The results also s upport the concept that neuroprotective strategies, which combine drugs wit h different mechanisms of action, may yield cumulative benefits. (C) 2000 E lsevier Science B.V. All rights reserved.