Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury

Abstract Ischemia–reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke. Cyclophilin D (CypD)-mediated openings of mitochondrial permeability transition pore (mPTP) and subsequent monocyte-mediated inflammation are considered as major mechanisms of reperfusion injury....

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Autores principales:	Arihide Okahara, Jun-ichiro Koga, Tetsuya Matoba, Masaki Fujiwara, Masaki Tokutome, Gentaro Ikeda, Kaku Nakano, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Hiroyuki Tsutsui, Kensuke Egashira
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/929409dd3f8a48648a7dd82691a4b1ce
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spelling	oai:doaj.org-article:929409dd3f8a48648a7dd82691a4b1ce2021-12-02T19:09:30ZSimultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury10.1038/s41598-020-71326-x2045-2322https://doaj.org/article/929409dd3f8a48648a7dd82691a4b1ce2020-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-71326-xhttps://doaj.org/toc/2045-2322Abstract Ischemia–reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke. Cyclophilin D (CypD)-mediated openings of mitochondrial permeability transition pore (mPTP) and subsequent monocyte-mediated inflammation are considered as major mechanisms of reperfusion injury. However, no medical therapies are currently available. Therefore, we have tested a hypothesis that simultaneous targeting of mPTP and inflammation confers substantial neuroprotection after cerebral ischemia–reperfusion. To address this point, we prepared CypD knockout mice, C–C chemokine receptor 2 (CCR2) knockout mice and CypD/CCR2 double knockout mice. These mice were subjected to 60 min transient cerebral ischemia by occluding middle cerebral arteries. Neurological deficits evaluated 3 days after reperfusion were significantly attenuated in CypD/CCR2 double knockout mice as compared to wild-type mice and other single knockout mice. Then, we have prepared polymeric nanoparticles containing cyclosporine A (CsA-NPs) and pitavastatin (Pitava-NPs), targeting mPTP opening and inflammation, respectively. Simultaneous administration of CsA-NP and Pitava-NP at the time of reperfusion also decreased infarct size and attenuated neurological deficits as compared to control nanoparticles and single administration of CsA-NPs or Pitava-NPs. These results indicate that simultaneous targeting of the mPTP opening and monocyte-mediated inflammation could be a novel strategy for better neurological outcomes in patients with ischemic stroke.Arihide OkaharaJun-ichiro KogaTetsuya MatobaMasaki FujiwaraMasaki TokutomeGentaro IkedaKaku NakanoMasaki TachibanaTetsuro AgoTakanari KitazonoHiroyuki TsutsuiKensuke EgashiraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arihide Okahara Jun-ichiro Koga Tetsuya Matoba Masaki Fujiwara Masaki Tokutome Gentaro Ikeda Kaku Nakano Masaki Tachibana Tetsuro Ago Takanari Kitazono Hiroyuki Tsutsui Kensuke Egashira Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
description	Abstract Ischemia–reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke. Cyclophilin D (CypD)-mediated openings of mitochondrial permeability transition pore (mPTP) and subsequent monocyte-mediated inflammation are considered as major mechanisms of reperfusion injury. However, no medical therapies are currently available. Therefore, we have tested a hypothesis that simultaneous targeting of mPTP and inflammation confers substantial neuroprotection after cerebral ischemia–reperfusion. To address this point, we prepared CypD knockout mice, C–C chemokine receptor 2 (CCR2) knockout mice and CypD/CCR2 double knockout mice. These mice were subjected to 60 min transient cerebral ischemia by occluding middle cerebral arteries. Neurological deficits evaluated 3 days after reperfusion were significantly attenuated in CypD/CCR2 double knockout mice as compared to wild-type mice and other single knockout mice. Then, we have prepared polymeric nanoparticles containing cyclosporine A (CsA-NPs) and pitavastatin (Pitava-NPs), targeting mPTP opening and inflammation, respectively. Simultaneous administration of CsA-NP and Pitava-NP at the time of reperfusion also decreased infarct size and attenuated neurological deficits as compared to control nanoparticles and single administration of CsA-NPs or Pitava-NPs. These results indicate that simultaneous targeting of the mPTP opening and monocyte-mediated inflammation could be a novel strategy for better neurological outcomes in patients with ischemic stroke.
format	article
author	Arihide Okahara Jun-ichiro Koga Tetsuya Matoba Masaki Fujiwara Masaki Tokutome Gentaro Ikeda Kaku Nakano Masaki Tachibana Tetsuro Ago Takanari Kitazono Hiroyuki Tsutsui Kensuke Egashira
author_facet	Arihide Okahara Jun-ichiro Koga Tetsuya Matoba Masaki Fujiwara Masaki Tokutome Gentaro Ikeda Kaku Nakano Masaki Tachibana Tetsuro Ago Takanari Kitazono Hiroyuki Tsutsui Kensuke Egashira
author_sort	Arihide Okahara
title	Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
title_short	Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
title_full	Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
title_fullStr	Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
title_full_unstemmed	Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
title_sort	simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/929409dd3f8a48648a7dd82691a4b1ce
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Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury

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