Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species.
Clomethiazole (CMZ) (Zendra) is neuroprotective in rodents following focal and global ischemia. However, its neuroprotective effects in other species, particularly on functional outcome, have not been reported. We have therefore examined the ability of CMZ to ameliorate the functional deficits produced by a focal cerebral ischemic lesion in the marmoset, a New World primate. Six monkeys received permanent middle cerebral artery occlusion (pMCAO); six further monkeys received pMCAO with administration of CMZ, 5 min after the arterial occlusion, by intraperitoneal bolus injection and by subcutaneous implantation of an osmotic minipump, which released CMZ for 24 h. The monkeys were trained and tested preoperatively on a number of behavioral tasks which were repeated 3 and 9 weeks after surgery. CMZ-treated monkeys were better than non-drug-treated monkeys at using the disabled arm contralateral to the lesion and also showed a reduction in contralateral spatial hemineglect. Postmortem histopathological analysis at several stereotaxic levels showed a significant reduction in the area of ischemic damage in CMZ-treated monkeys compared to that in untreated animals. CMZ treatment reduced the overall volume of damage by 31.8% (MCA group, 370.8 +/- 37.4 mm3 of damage; CMZ group, 253.0 +/- 38.0 mm3 of damage). This study demonstrates that CMZ is neuroprotective in a nonhuman primate species and is able to ameliorate the level of functional disability and reduce the size of infarct produced by focal cerebral ischemia.
Marshall
J W
JW
Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, United Kingdom.
Cross
A J
AJ
Ridley
R M
RM
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature; D001921:Brain / Q000473:pathology; D002144:Callithrix; D002539:Cerebral Arterial Diseases / Q000150:complications; D002719:Chlormethiazole / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D012399:Rotation
D018696:Neuroprotective Agents; D002719:Chlormethiazole