Neuroprotection against cerebral ischemia/reperfusion injury by intravenous administration of liposomal fasudil.
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.
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
Tatsuya
T
Fukuta
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Tomohiro
T
Asai
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Akihiko
A
Sato
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Mio
M
Namba
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Yosuke
Y
Yanagida
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Takashi
T
Kikuchi
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Hiroyuki
H
Koide
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Kosuke
K
Shimizu
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
Naoto
N
Oku
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008081:Liposomes / Q000008:administration & dosage*; D008297:Male; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D020521:Stroke / Q000188:drug therapy
D008081:Liposomes; D018696:Neuroprotective Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil
Blood–brain barrier; Cerebral ischemia/reperfusion injury; Fasudil; Ischemic stroke; Liposomes; Middle cerebral artery occlusion