title: The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia-reperfusion injury both in vitro and in vivo: Involvement of BK channels.
abstract: Mitochondrial division inhibitor (mdivi-1), a selective inhibitor of a mitochondrial fission protein dynamin-related protein 1 (Drp1), has been shown to exert protective effects in heart and cerebral ischemia-reperfusion models. The present study was designed to investigate the beneficial effects of mdivi-1 against spinal cord ischemia-reperfusion (SCIR) injury and its associated mechanisms. SCIR injury was induced by glutamate treatment in cultured spinal cord neurons and by descending thoracic aorta occlusion for 20 min in rats. We found that mdivi-1 (10 μM) significantly attenuated glutamate induced neuronal injury and apoptosis in spinal cord neurons. This neuroprotective effect was accompanied by decreased expression of oxidative stress markers, inhibited mitochondrial dysfunction and preserved activities of antioxidant enzymes. In addition, mdivi-1 significantly increased the expression of the large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels, and blocking BK channels by paxilline partly ablated mdivi-1 induced protection. The in vivo experiments showed that mdivi-1 treatment (1 mg/kg) overtly mitigated SCIR injury induced spinal cord edema and neurological dysfunction with no organ-related toxicity in rats. Moreover, mdivi-1 increased the expression of BK channels in spinal cord tissues, and paxilline pretreatment nullified mdivi-1 induced protection after SCIR injury in rats. Thus, mdivi-1 may be an effective therapeutic agent for SCIR injury via activation of BK channels as well as reduction of oxidative stress, mitochondrial dysfunction and neuronal apoptosis. This article is part of a Special Issue entitled SI: Spinal cord injury.
authors.affiliation: Department of Emergency, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China.
authors.forename: Shi-Zhang
authors.initials: SZ
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Shaanxi Provincial People's Hospital, The Third affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Department of Emergency, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China.
authors.forename: Xing-Bo
authors.initials: XB
authors.lastname: Dang
authors.affiliation: Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China.
authors.forename: Quan-Yi
authors.initials: QY
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Shaanxi Provincial People's Hospital, The Third affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710068, Shaanxi, China. Electronic address: zhangyuelin_xjtu@163.com.
authors.forename: Yue-Lin
authors.initials: YL
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D034281:Dynamins / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D052999:Quinazolinones / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020760:Spinal Cord Ischemia / Q000378:metabolism / Q000517:prevention & control*
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D051036:Large-Conductance Calcium-Activated Potassium Channels; D052999:Quinazolinones; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: BK channels; Mdivi-1; Mitochondrial dysfunction; Mitochondrial fission; Spinal cord ischemia–reperfusion injury