Combined neuroprotection and reperfusion therapy for stroke - Effect of lubeluzole and diaspirin cross-linked hemoglobin in experimental focal ischemia

Background and Purpose In search of a better treatment for acute ischemic stroke, we evaluated the use of lubeluzole and hemodilution with diaspirin cross-linked hemoglobin (DCLHb) therapy to test whether treatment with two complementary acting compounds provides more potent protection than either treatment alone. Methods We used unilateral reversible middle cerebral artery (MCA) and common carotid artery (CCA) occlusion of various durations in Long-Evans rats to produce ischemic cortical lesions. We calculated the average maximal lesion volume (Vol(max)) and the time required to produce half maximal lesion size (T-50) in control animals (n=31) and evaluated the effects on cerebral perfusion and infarct size of treatment with lubeluzole (n=23). hemodilution (to 30% hematocrit) with albumin (n=17) or DCLHb (n=23), and combined lubeluzole + DCLHb therapy initiated 15 minutes after MCA/CCA occlusion. Results The Vol(max) produced by MCA/CCA occlusion in control animals was 138.5 +/- 7.7 mm(3), and T-50 was 98.5 +/- 10.2 minutes. Lubeluzole alone reduced Vol(max) by 53% with no significant effect on T-50. In contrast to lubeluzole, DCLHb hemodilution prolonged T-50 by 68% with no significant effect on Vol(max). Prolongation of T-50 by DCLHb was not due to hemodilution itself, since a similar degree of hemodilution with albumin had no effect. Finally, combined lubeluzole + DCLHb rescued 72% of the tissue and augmented the effect of lubeluzole alone by 40% (Vol(max) 66.3 +/- 13.0 versus 39.4 +/- 12.2 mm(3)) while prolonging T-50 by 31%. Conclusions Combination therapy for acute stroke using compounds with complementary action can result in more complete attenuation of neuronal damage and demonstrates the possible clinical utility of combined neuroprotective and reperfusion therapies.