Combined neuroprotection and reperfusion therapy for stroke. Effect of lubeluzole and diaspirin cross-linked hemoglobin in experimental focal ischemia.
OBJECTIVE
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 (Volmax) and the time required to produce half maximal lesion size (T50) 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 Volmax produced by MCA/CCA occlusion in control animals was 138.5 +/- 7.7 mm3, and T50 was 98.5 +/- 10.2 minutes. Lubeluzole alone reduced Volmax by 53% with no significant effect on T50. In contrast to lubeluzole, DCLHb hemodilution prolonged T50 by 68% with no significant effect on Volmax. Prolongation of T50 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% (Volmax, 66.3 +/- 13.0 versus 39.4 +/- 12.2 mm3) while prolonging T50 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.
Aronowski
J
J
Department of Neurology, University of Texas Medical School, Houston 77030, USA.
Strong
R
R
Grotta
J C
JC
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000097:blood / Q000628:therapy*; D004359:Drug Therapy, Combination; D006438:Hemodilution; D006454:Hemoglobins / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D015424:Reperfusion; D013844:Thiazoles / Q000627:therapeutic use*
D002317:Cardiovascular Agents; D006454:Hemoglobins; D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin; C097722:lubeluzole