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- Title
Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia–reperfusion injury.
- Authors
Okahara, Arihide; Koga, Jun-ichiro; Matoba, Tetsuya; Fujiwara, Masaki; Tokutome, Masaki; Ikeda, Gentaro; Nakano, Kaku; Tachibana, Masaki; Ago, Tetsuro; Kitazono, Takanari; Tsutsui, Hiroyuki; Egashira, Kensuke
- 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.
- Subjects
MITOCHONDRIA; MONOCYTES; ISCHEMIA; REPERFUSION injury; NANOPARTICLES
- Publication
Scientific Reports, 2020, Vol 10, Issue 1, pN.PAG
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-020-71326-x