title: Tacrolimus, a potential neuroprotective agent, ameliorates ischemic brain damage and neurologic deficits after focal cerebral ischemia in nonhuman primates.
abstract: 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.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan. yasuhisa_furuichi@po.fujisawa.co.jp
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Furuichi
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.forename: Akio
authors.initials: A
authors.lastname: Kawamura
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yanagihara
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008252:Macaca fascicularis; D008297:Male; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics*; D020127:Recovery of Function / Q000187:drug effects; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D016559:Tacrolimus