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....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2020-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-71326-x |
| _version_ | 1818423130054459392 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T13:37:15Z |
| format | Article |
| id | doaj.art-929409dd3f8a48648a7dd82691a4b1ce |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T13:37:15Z |
| publishDate | 2020-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-929409dd3f8a48648a7dd82691a4b1ce2022-12-21T22:59:34ZengNature PortfolioScientific Reports2045-23222020-09-0110111410.1038/s41598-020-71326-xSimultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injuryArihide Okahara0Jun-ichiro Koga1Tetsuya Matoba2Masaki Fujiwara3Masaki Tokutome4Gentaro Ikeda5Kaku Nakano6Masaki Tachibana7Tetsuro Ago8Takanari Kitazono9Hiroyuki Tsutsui10Kensuke Egashira11Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Research, Development, and Translational Medicine, Center for Cardiovascular Disruptive Innovation, Kyushu UniversityDepartment of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Cardiovascular Research, Development, and Translational Medicine, Center for Cardiovascular Disruptive Innovation, Kyushu UniversityAbstract 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.https://doi.org/10.1038/s41598-020-71326-x |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-020-71326-x |
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