pitavastatin and Infarction--Middle-Cerebral-Artery

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.

Topics: Animals; Cyclosporine; Drug Combinations; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Permeability Transition Pore; Monocytes; Nanoparticles; Neuroprotective Agents; Peptidyl-Prolyl Isomerase F; Quinolines; RAW 264.7 Cells; Receptors, CCR2

This study aimed to clarify the effect of statins on spontaneous stroke and to examine the antioxidative effect in artificial transient middle cerebral artery occlusion (tMCAO).. Stroke-prone spontaneous hypertensive rats (SHR-SP) were treated with pitavastatin, atorvastatin, simvastatin, or vehicle for 4 weeks. Physiological parameters, serum lipids, and infarct volumes were examined. The markers for oxidative stresses on lipids and DNA were immunohistochemically detected in vehicle-treated or simvastatin-treated SHR-SP with tMCAO.. Atorvastatin and simvastatin decreased infarct volumes, with simvastatin most effective. Simvastatin significantly reduced immunoreactivities for oxidative stress markers for lipids and DNA in neurons after tMCAO.. The results suggest that the antioxidative properties of statins may be implicated in their beneficial effects against neuronal damage in cerebral ischemia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Atorvastatin; Blood Pressure; Body Weight; Deoxyguanosine; Disease Models, Animal; Heptanoic Acids; Hydroxymethylglutaryl CoA Reductases; Infarction, Middle Cerebral Artery; Lipids; Lysine; Oxidative Stress; Pyrroles; Quinolines; Rats; Rats, Inbred SHR; Simvastatin; Survival Analysis