title: Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506.
abstract: FK506 (Tacrolimus) has the potential to decrease cerebral ischemia-reperfusion injury. However, the clinical trial of FK506 as a neuroprotectant failed due to adverse side effects. This present study aimed to conduct the selective delivery of FK506 to damaged regions, while at the same time reducing the dosage of FK506, by using a liposomal drug delivery system. First, the cytoprotective effect of polyethylene glycol-modified liposomes encapsulating FK506 (FK506-liposomes) on neuron-like pheochromocytoma PC12 cells was examined. FK506-liposomes protected these cells from H2O2-induced toxicity in a dose-dependent manner. Next, we investigated the usefulness of FK506-liposomes in transient middle cerebral artery occlusion (t-MCAO) rats. FK506-liposomes accumulated in the brain parenchyma by passing through the disrupted blood-brain barrier at an early stage after reperfusion had been initiated. Histological analysis showed that FK506-liposomes strongly suppressed neutrophil invasion and apoptotic cell death, events that lead to a poor stroke outcome. Corresponding to these results, a single injection of FK506-liposomes at a low dosage significantly reduced cerebral cell death and ameliorated motor function deficits in t-MCAO rats. These results suggest that liposomalization of FK506 could reduce the administration dose by enhancing the therapeutic efficacy; hence, FK506-liposomes should be a promising neuroprotectant after cerebral stroke.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishii
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.forename: Dai
authors.initials: D
authors.lastname: Oyama
authors.forename: Yurika
authors.initials: Y
authors.lastname: Agato
authors.forename: Nodoka
authors.initials: N
authors.lastname: Yasuda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukuta
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shimizu
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D002546:Ischemic Attack, Transient / Q000188:drug therapy; D008081:Liposomes / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D008081:Liposomes; D018696:Neuroprotective Agents; D006861:Hydrogen Peroxide; D016559:Tacrolimus