title: Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor γ coactivator-1α signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia.
abstract: Delayed neuronal cell death occurs in the vulnerable CA1 subfield of the hippocampus after transient global ischemia (TGI). We demonstrated previously, based on an experimental model of TGI, that the significantly increased content of oxidized proteins in hippocampal CA1 neuron was observed as early as 30 min after TGI, followed by augmentation of PGC-1α expression at 1 hr, as well as up-regulation of mitochondrial uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2). Using the same animal model, the present study investigated the role of calcium/calmodulin-dependent protein kinase IV (CaMKIV) and PGC-1α in delayed neuronal cell death and mitochondrial biogenesis in the hippocampus. In Sprague-Dawley rats, significantly increased expression of nuclear CaMKIV was noted in the hippocampal CA1 subfield as early as 15 min after TGI. In addition, the index of mitochondrial biogenesis, including a mitochondrial DNA-encoded polypeptide, cytochrome c oxidase subunit 1 (COX1), and mitochondrial number significantly increased in the hippocampal CA1 subfield 4 hr after TGI. Application bilaterally into the hippocampal CA1 subfield of an inhibitor of CaMKIV, KN-93, 30 min before TGI attenuated both CaMKIV and PGC-1α expression, followed by down-regulation of UCP2 and SOD2, decrease of COX1 expression and mitochondrial number, heightened protein oxidation, and enhanced hippocampal CA1 neuronal damage. This study provides correlative evidence for the neuroprotective cascade of CaMKIV/PGC-1α which implicates at least in part the mitochondrial antioxidants UCP2 and SOD2 as well as mitochondrial biogenesis in ischemic brain injury.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shang-Der
authors.initials: SD
authors.lastname: Chen
authors.forename: Tsu-Kung
authors.initials: TK
authors.lastname: Lin
authors.forename: Jui-Wei
authors.initials: JW
authors.lastname: Lin
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Lee
authors.forename: Fu-Zen
authors.initials: FZ
authors.lastname: Shaw
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Liou
authors.forename: Yao-Chung
authors.initials: YC
authors.lastname: Chuang
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D000099156:Superoxide Dismutase 2
chemical_list: D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000071246:Uncoupling Protein 2; D000099156:Superoxide Dismutase 2; C501429:Ppargc1a protein, rat; C000604391:Ucp2 protein, rat; C517686:Camk4 protein, rat