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. 2016 Jun 15;506(1-2):129-37.
doi: 10.1016/j.ijpharm.2016.04.046. Epub 2016 Apr 20.

Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil

Tatsuya Fukuta  1 , Tomohiro Asai  2 , Akihiko Sato  2 , Mio Namba  2 , Yosuke Yanagida  2 , Takashi Kikuchi  2 , Hiroyuki Koide  2 , Kosuke Shimizu  2 , Naoto Oku  3
Affiliations

Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil

Tatsuya Fukuta et al. Int J Pharm. .

Abstract

Fasudil, a Rho-kinase inhibitor, is a promising neuroprotectant against ischemic stroke; however, its low bioavailability is an obstacle to be overcome. Our previous study revealed that the liposomal drug delivery system is a hopeful strategy to increase the therapeutic efficacy of neuroprotectants. In the present study, the usefulness of intravenously administered liposomal fasudil for cerebral ischemia/reperfusion (I/R) injury treatment was examined in transient middle cerebral artery occlusion (t-MCAO) rats. The results showed that PEGylated liposomes of approximately 100nm in diameter accumulated more extensively in the I/R region compared with those of over 200nm. Confocal images showed that fluorescence-labeled liposomal fasudil was widely distributed in the I/R region, and was not noticeably taken up by microglia, which are well-known resident macrophages in the brain, and neuronal cells. These data indicated that liposomal fasudil mainly exerted its pharmacological activity by releasing fasudil from the liposomes in the I/R region. Moreover, liposomal fasudil effectively suppressed neutrophil invasion and brain cell damage in the t-MCAO rats, resulting in amelioration of their motor function deficits. These findings demonstrated both the importance of particle size for neuroprotectant delivery and the effectiveness of liposomal fasudil for the treatment of cerebral I/R injury.

Keywords: Blood–brain barrier; Cerebral ischemia/reperfusion injury; Fasudil; Ischemic stroke; Liposomes; Middle cerebral artery occlusion.

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