title: Multiple modes of action of tacrolimus (FK506) for neuroprotective action on ischemic damage after transient focal cerebral ischemia in rats.
abstract: While the immunosuppressant tacrolimus (FK506) is known to be neuroprotective following cerebral ischemia, the mechanisms underlying its neuroprotective properties are not fully understood. To determine the mode of action by which tacrolimus ameliorates neurodegeneration after transient focal ischemia, we therefore evaluated the effect of tacrolimus on DNA damage, release of cytochrome c, activation of microglia and infiltration of neutrophils following a 60-min occlusion of the middle cerebral artery (MCA) in rats. In this model, cortical brain damage gradually expanded until 24 h after reperfusion, whereas brain damage in the caudate putamen was fully developed within 5 h. Tacrolimus (1 mg/kg) administered immediately after MCA occlusion significantly reduced ischemic damage in the cerebral cortex, but not in the caudate putamen. Tacrolimus decreased both apoptotic and necrotic cell death at 24 h and reduced the number of cytochrome c immunoreactive cells at 8 h after reperfusion in the ischemic penumbra in the cerebral cortex. In contrast, tacrolimus did not show significant neuroprotection for necrotic cell death and reduction of cytochrome c immunoreactive cells in the caudate putamen. Tacrolimus also significantly decreased microglial activation at 8 h and inflammatory markers (cytokine-induced neutrophil chemoattractant and myeloperoxidase [MPO] activity) at 24 h after reperfusion in the ischemic cortex but not in the caudate putamen. These results collectively suggest that tacrolimus ameliorates the gradually expanded brain damage by inhibiting both apoptotic and necrotic cell death, as well as suppressing inflammatory reactions.
authors.affiliation: Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, 2-1-6, Kashima, Osaka 532-8514, Japan. yasuhisa_furuichi@po.fujisawa.co.jp
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Furuichi
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.forename: Ji-Yao
authors.initials: JY
authors.lastname: Li
authors.forename: Takuma
authors.initials: T
authors.lastname: Oku
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishiye
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aramori
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; D017209:Apoptosis / Q000187:drug effects; D002421:Caudate Nucleus / Q000473:pathology; D019743:Chemokines, CXC / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D045304:Cytochromes c; D009195:Peroxidase; D016559:Tacrolimus