title: Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. macke009@mc.duke.edu
authors.forename: G B
authors.initials: GB
authors.lastname: Mackensen
authors.forename: B
authors.initials: B
authors.lastname: Nellgård
authors.forename: S
authors.initials: S
authors.lastname: Sarraf-Yazdi
authors.forename: F
authors.initials: F
authors.lastname: Dexter
authors.forename: R P
authors.initials: RP
authors.lastname: Steffen
authors.forename: H P
authors.initials: HP
authors.lastname: Grocott
authors.forename: D S
authors.initials: DS
authors.lastname: Warner
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use*; D000818:Animals; D001784:Blood Gas Analysis; D001831:Body Temperature; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004357:Drug Synergism; D006454:Hemoglobins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009460:Neurologic Examination / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011422:Propionates / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D006454:Hemoglobins; D018696:Neuroprotective Agents; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C067396:efaproxiral