Tacrolimus (
FK506), an immunosuppressive
drug, is known to have potent neuroprotective activity and attenuate
cerebral infarction in experimental models of
stroke. Here we assess the neuroprotective efficacy of
tacrolimus in a nonhuman primate model of
stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment,
tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and
neurologic deficits and
cerebral infarction volumes were assessed 24 hours after the ischemic insult.
Tacrolimus dose-dependently reduced
neurologic deficits and
infarction volume in the cerebral cortex, with statistically significant amelioration of
neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of
infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of
tacrolimus on
neurologic deficits and
cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of
tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of
neurologic deficits and significant reduction of
infarction volume. In conclusion, we have provided compelling evidence that a single dose of
tacrolimus not only reduces
brain infarction but also ameliorates long-term
neurologic deficits in a nonhuman primate model of
stroke, strengthening the view that
tacrolimus might be beneficial in treating
stroke patients.