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.
Highlights
Ischemia–reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke
The neurological deficit score was significantly reduced both in Cyclophilin D (CypD)-KO and DKO mice at day 1; a significant reduction of the score was observed only in DKO mice at day 3 (Fig. 1B), which suggests that the blockade of either CypD or chemokine receptor 2 (CCR2) is insufficient, and simultaneous targeting of both CypD and CCR2, i.e. both mitochondrial permeability transition pore (mPTP) opening and inflammation, is necessary to improve neurological outcomes after cerebral IR injury
These results indicate that the leakage of cytochrome c from the mitochondria is mainly regulated by CypD in the super acute phase after IR injury (30 min)
Summary
Ischemia–reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke. 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. The revascularization after cerebral infarction is becoming a common procedure This progress raises a possibility that drugs which could not show their efficacy in past clinical trials exert their therapeutic effects in the current era of early reperfusion therapy by combining with appropriate DDS. We have performed transient occlusion of middle cerebral artery to simulate cerebral ischemia and early reperfusion In this model, we have tested an efficacy of simultaneous administration of CsA-NP and Pitava-NP on infarct size and neurological outcomes after cerebral IR
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