title: Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy.
abstract: 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.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-Ku, Osaka 532-8514, Japan. yasuhisa_furuichi@po.fujisawa.co.jp
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Furuichi
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Katsuta
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.forename: Noriko
authors.initials: N
authors.lastname: Ueyama
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Toshio
authors.initials: T
authors.lastname: Goto
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yanagihara
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002452:Cell Count / Q000379:methods; D004305:Dose-Response Relationship, Drug; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D016559:Tacrolimus