Tacrolimus (FK506) ameliorates skilled motor deficits produced by middle cerebral artery occlusion in rats.
OBJECTIVE
Tacrolimus (FK506) is a potent immunosuppressant that is presently in clinical use for prevention of allograft rejection. Recently, animal studies reporting significant reductions in the volume of tissue damage associated with cardiac, hepatic, and cerebral ischemia suggest that tacrolimus may also be of use in the clinical management of stroke. In the present study, we examine whether the neuroprotective effects of tacrolimus, as assessed by histological outcome, are accompanied by an amelioration of the skilled motor deficits induced in the rat by middle cerebral artery occlusion (MCAO).


METHODS
Animals were trained to perform a skilled paw-reaching task before MCAO by perivascular microinjections of endothelin-1. Tacrolimus (1 mg/kg, n = 6) or vehicle (n = 6) was administered by intravenous infusion 1 minute after MCAO. After a 5-day postoperative recovery period, the rats were retested for skilled paw-reaching ability for an additional 9 days.


RESULTS
In vehicle-treated rats, MCAO resulted in a profound bilateral impairment in skilled paw use. Rats treated with tacrolimus, although still impaired, performed significantly better than those treated with vehicle alone (P < .01). Histological analysis, 14 days after occlusion, confirmed the neuroprotective efficacy of tacrolimus with a 66% reduction in the volume of hemispheric brain damage produced by MCAO (P < .01).


CONCLUSIONS
The present studies show that tacrolimus not only protects neural tissue from focal cerebral ischemia but also significantly ameliorates the deficits in skilled motor ability produced by this lesion. These data provide further support for the view that tacrolimus may be of use in the treatment of stroke.
Sharkey
J
J
Fujisawa Institute of Neuroscience, University of Edinburgh, UK. j.sharkey@ed.ac.uk
Crawford
J H
JH
Butcher
S P
SP
Marston
H M
HM
D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002536:Cerebral Arteries; D003250:Constriction; D019332:Endothelin-1 / Q000633:toxicity; D008297:Male; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*
D019332:Endothelin-1; D018696:Neuroprotective Agents; D016559:Tacrolimus