title: Penehyclidine hydrochloride postconditioning ameliorates cerebral ischemia-reperfusion injury: critical role of mitochondrial ATP sensitive potassium channel.
abstract: Cerebral ischemia/reperfusion (CI/R) leads to disability and death worldwide. However, limited approaches have been made in developing therapies to decrease the detrimental effects of CI/R. In the present study, we evaluated the effects of penehyclidine hydrochloride (PHC) postconditioning on CI/R injury and elucidated the underlying mechanisms. In CI/R rats, we showed that PHC postconditioning could effectively inhibit I/R-induced brain infarction and edema, and deficit of neurological function. In addition, PHC postconditioning significantly inhibited I/R-induced increase of proinflammatory cytokines and TUNEL-positive cell numbers. Moreover, the opening of mitochondrial permeability transition pore (mPTP) and oxidative stress resulting from I/R were suppressed notably by PHC postconditioning, as evidenced by increased absorbance at 540 nm in Ca2+-induced mitochondrial swelling test and increased SOD activity and decreased ROS and MDA level. 5-hydroxydecanoate (5-HD), a specific inhibitor of MitoKATP, was used to evaluate the role of MitoKATP in the neuroprotective effect of PHC postconditioning. The results showed that 5-HD could markedly suppress PHC postconditioning-caused inhibition of brain infarction and edema, deficit of neurological function, inflammation, apoptosis, opening of mPTP and oxidative stress induced by CI/R. The results demonstrated that PHC postconditioning could protect against I/R injury in brain through the inhibition of oxidative stress, mPTP opening, apoptosis and inflammation. Activation of MitoKATP was critical for PHC postconditioning-exhibited neuro-protective effects against I/R injury. These findings may provide a novel foundation for therapeutic strategies targeting cerebral protection against I/R damage.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Xian Medical University, Xian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Emergency Department, The First Affiliated Hospital of Xian Medical University, Xian, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Xian Medical University, Xian, China.
authors.forename: B
authors.initials: B
authors.lastname: Han
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D016207:Cytokines / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D057775:Ischemic Postconditioning; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008959:Models, Neurological; D018384:Oxidative Stress / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D011812:Quinuclidines; C117780:mitochondrial K(ATP) channel; C486140:penehyclidine