TACROLIMUS (FK506) AMELIORATES SKILLED MOTOR DEFICITS PRODUCED BY MIDDLE CEREBRAL-ARTERY OCCLUSION IN RATS

Background and Purpose Tacrolimus (FK506) is a potent immunosuppressan t that is presently in clinical use for prevention of allograft reject ion. Recently, animal studies reporting signifi cant reductions in the volume of tissue damage associated with cardiac, hepatic, and cerebra l ischemia suggest that tacrolimus may also be of use in the clinical management of stroke. In the present study, we examine whether the neu roprotective effects of tacrolimus, as assessed by histological outcom e, are accompanied by an amelioration of the skilled motor deficits in duced in the rat by middle cerebral artery occlusion (MCAO). Methods A nimals were trained to perform a skilled paw-reaching task before MCAO by perivascular microinjections of endothelin-l. Tacrolimus (1 mg/kg, n=6) or vehicle (n=6) was administered by intravenous infusion 1 minu te after MCAO. After a 5-day postoperative recovery period, the rats w ere retested for skilled paw-reaching ability for an additional 9 days . Results In vehicle-treated rats, MCAO resulted in a profound bilater al impairment in skilled paw use. Rats treated with tacrolimus, althou gh still impaired, performed significantly better than those treated w ith vehicle alone (P<.01). Histological analysis, 14 days after occlus ion, confirmed the neuroprotective efficacy of tacrolimus with a 66% r eduction in the volume of hemispheric brain damage produced by MCAO (P <.01). Conclusions The present studies show that tacrolimus not only p rotects neural tissue from focal cerebral ischemia but also significan tly ameliorates the deficits in skilled motor ability produced by this lesion. These data provide further support for the view that tacrolim us may be of use in the treatment of stroke.