Tacrolimus (
FK506), a potent immunosuppressive
drug, is effective in attenuating
brain infarction after
cerebral ischemia. However, there has been no report characterizing the neuroprotective action and therapeutic time window of
tacrolimus systematically using different types of
stroke models and extended observation periods. Therefore, we evaluated the
neuroprotective effect of
tacrolimus in three different animal models of
cerebral ischemia: transient and permanent focal
ischemia in rats and transient global
ischemia in gerbils.
Tacrolimus at doses higher than 0.1 mg/kg (i.v.) produced a statistically significant reduction in ischemic brain damage following permanent and transient focal
ischemia in rats when administered immediately after the onset of
ischemia.
Tacrolimus (1 mg/kg, i.v.) demonstrated similar neuroprotective activity even after delayed administration (2 h after permanent or 1 h after transient focal
ischemia). The
neuroprotective effect of
tacrolimus was still present 2 weeks after transient focal
ischemia and 1 week after permanent focal
ischemia. After transient global
ischemia in gerbils,
tacrolimus (1 mg/kg, i.v.) given immediately after reperfusion also produced long-lasting
neuroprotective effects with a protective time-window of 1-2 h. Taken together, the results clearly indicate that
tacrolimus exerts potent, long-term
neuroprotective effects with a favorable therapeutic time-window, regardless of the model of
cerebral ischemia. These results strengthen the notion that
tacrolimus might be of clinical value for the treatment of
acute stroke.