Transdermal System Based on Solid Cilostazol Nanoparticles Attenuates Ischemia/Reperfusion-Induced Brain Injury in Mice.

Hiroko Otake,Naohito Kawasaki,Saori Deguchi,Mizuki Yamaguchi,Hiroshi Sasaki,Noriaki Nagai,Fumihiko Ogata,Naoki Yamamoto

doi:10.3390/nano11041009

Hiroko Otake, Naohito Kawasaki + Show 6 more

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https://doi.org/10.3390/nano11041009

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Journal: Nanomaterials	Publication Date: Apr 15, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Kindai University, Kanazawa Medical University

Abstract

Cilostazol (CIL) exerted a protective effect by promoting blood–brain barrier integrity as well as improving the status of neurological dysfunctions following cerebral ischemia/reperfusion (I/R) injury. We attempted to design a 0.5% CIL carbopol gel using solid nanoparticles (CIL-Ngel), and then investigated the relationships between energy-dependent endocytosis and the skin penetration of CIL-Ngel in this study. In addition, we evaluated whether the CIL-Ngel attenuated I/R-induced brain injury in a middle cerebral artery occlusion (MCAO)/reperfusion model mouse. The particle size of CIL was decreased using a bead mill, and the CIL particles (14.9 × 1014 particles/0.3 g) in the CIL-Ngel were approximately 50–180 nm. The release of CIL in the CIL-Ngel was higher than that in gel containing CIL powder (CIL-Mgel), and the CIL particles were released from the CIL-Ngel as nanoparticles. In addition, the percutaneous absorption of CIL from the CIL-Ngel was higher in comparison with that from CIL-Mgel, and clathrin-dependent endocytosis and caveolae-dependent endocytosis were related to the enhanced skin penetration of CIL-NPs. In the traditional (oral administration of CIL powder, 3 mg/kg) and transdermal administration (CIL-Ngel, 0.3 g) for 3 days (once a day), the area under the plasma CIL concentration–time curves (AUC) was similar, although the CIL supplied to the blood by the CIL-Ngel was more sustained than that via oral administration of CIL powder. Furthermore, the CIL-Ngel attenuated the ischemic stroke. In conclusion, we designed a gel using solid CIL-NPs, and we showed that the sustained release of CIL by CIL-Ngel provided an effective treatment for ischemic stroke in MCAO/reperfusion model mice. These findings induce the possibilities of developing novel applications of CIL solid nanoparticles.

Highlights

Introduction published maps and institutional affilAn ischemic stroke represents the onset of a high-mortality disease and enhances social burden and causes economic disability for countries and communities
We reported that the oral or intravenous administration of CIL solid nanoparticles (CIL-NPs) prevented I/R-induced brain injury in a middle cerebral artery occlusion (MCAO)/reperfusion model mouse [13,14]
CIL, CIL, 6-[4-(1-cyclohexyl-1H-tetrazol-5yl)butoxy]-3, 6-[4-(1-cyclohexyl-1H-tetrazol-5yl)butoxy]-3, 4-dihydro-2(1H)-quiolinone, 4-dihydro-2(1H)-quiolinone, can can decrease the degree of neuronal cell death following transient decrease the degree of neuronal cell death following transient cerebral cerebral ischemia ischemia [28]

Summary

Introduction

An ischemic stroke represents the onset of a high-mortality disease and enhances social burden and causes economic disability for countries and communities. Therapy for an ischemic stroke involves only an injection of tissue plasminogen activator (tPA), whereby the tPA dissolves any clots and restores blood supply [1]. The restoration of cerebral blood supply by tPA causes neuroinflammation and oxidative stress [2,3], and previous studies have reported that cerebral ischemia/reperfusion (I/R) induced excessive production of aggregating and misfolded proteins [4,5]. Jin et al reported that the inhibition of inflammation-related signaling pathways could reduce I/R injury and increase functional outcome in preclinical iations

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