Long term cerebroprotective effects of dexanabinol in a model of focal cerebral ischemia.
In order to test the long-term cerebroprotective effects of dexanabinol, a synthetic non-competitive NMDA antagonist that also has anti-TNFalpha effects, spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Rats were given vehicle or dexanabinol (4.5 mg/kg) 1, 3 or 6 h after PMCAO. The research consisted of 2 stages. In the short-term set of experiments animals (n=5/group), were tested with a motor disability scale 24 h post PMCAO, then sacrificed and the infarct volume was measured using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. In the long-term set of experiments the rats (n=7/group) were examined daily with a motor disability scale up to 30 days after PMCAO and then sacrificed and infarct volumes were determined using TTC staining. Motor scores were significantly improved in the dexanabinol treated rats (P<0.05 for all groups) at all the time points examined. Infarct volumes were significantly reduced 24 h after PMCAO in the groups treated 1 or 3 h, but not 6 h after PMCAO compared with vehicle (Mean+/-S.D., 11.5+/-2.02, 12+/-3.2 and 14.4+/-2.4% vs. 20.8+/-1.3% hemispheric volume respectively). The lesions remained significantly smaller in the dexanabinol groups 30 days after PMCAO (Mean+/-S.D., 24.49+/-1.9% vs. 8.1+/-0.6, 11.1+/-2.3 and 13.8+/-2.5% hemispheric volume in animals treated with vehicle vs. dexanabinol 1, 3 or 6 h after PMCAO respectively; P<0.05 for all). In conclusion, the extended therapeutic window and the multi-mechanistic durable neuroprotective effects of dexanabinol make it a promising candidate for future stroke therapy.
Lavie
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Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hebrew University-Hadassah Medical School, Hadassah University Hospital, Ein Kerem, P.O. Box 12000, 91120, Jerusalem, Israel.
Teichner
A
A
Shohami
E
E
Ovadia
H
H
Leker
R R
RR
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013778:Tetrazolium Salts / Q000493:pharmacokinetics
D005609:Free Radicals; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D013759:Dronabinol; C062018:HU 211