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Treatment of cerebral ischemia‐reperfusion injury with PEGylated liposomes encapsulating FK506
Author(s) -
Ishii Takayuki,
Asai Tomohiro,
Oyama Dai,
Agato Yurika,
Yasuda Nodoka,
Fukuta Tatsuya,
Shimizu Kosuke,
Minamino Tetsuo,
Oku Naoto
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-221325
Subject(s) - liposome , medicine , pharmacology , ischemia , drug delivery , stroke (engine) , neuroprotection , reperfusion injury , blood–brain barrier , anesthesia , central nervous system , chemistry , biochemistry , mechanical engineering , organic chemistry , engineering
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 H 2 O 2 ‐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.—Ishii, T., Asai, T., Oyama, D., Agato, Y., Yasuda, N., Fukuta, T., Shimizu, K., Minamino, T., Oku, N. Treatment of cerebral ischemia‐reperfusion injury with PEGylated liposomes encapsulating FK506. FASEB J. 27, 1362–1370 (2013). www.fasebj.org