title: Ischemic preconditioning protects the brain against injury via inhibiting CaMKII-nNOS signaling pathway.
abstract: Although studies have shown that cerebral ischemic preconditioning (IPC) can ameliorate ischemia/reperfusion (I/R) induced brain damage, but its precise mechanisms remain unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of IPC against ischemic brain damage induced by cerebral I/R and to explore whether the Calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway contributed to the protection provided by IPC. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with 3 min of IPC alone or KN62 (selective antagonist of CaMKII) treatment before IPC, after reperfusion for 3 days, 6 min ischemia was induced. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of CaMKII, nNOS, c-Jun and the expression of FasL. Immunoprecipitation was used to examine the binding between PSD95 and nNOS. The results showed that IPC could significantly protect neurons against cerebral I/R injury, furthermore, the combination of PSD95 and nNOS was increased, coinstantaneously the phosphorylation of CaMKII and nNOS (ser847) were up-regulated, however the activation of c-Jun and FasL were reduced. Conversely, KN62 treatment before IPC reversed all these effects of IPC. Taken together, the results suggest that IPC could diminish ischemic brain injury through CaMKII-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway.
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China; Laboratory of Morphology, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China; Department of Genetics, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Da-Shi
authors.initials: DS
authors.lastname: Qi
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Cui
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Endocrine, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, PR China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Li
authors.affiliation: Laboratory of Morphology, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Laboratory of Morphology, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Han
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Jie-Hui
authors.initials: JH
authors.lastname: Di
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Jun-Song
authors.initials: JS
authors.lastname: Ye
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China; Department of Genetics, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China. Electronic address: biosongyuanjian@126.com.
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Song
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu 221004, PR China. Electronic address: gyzhang@xzmc.edu.cn.
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D053222:Fas Ligand Protein / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019194:Ischemic Preconditioning; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052248:Nitric Oxide Synthase Type I; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048031:JNK Mitogen-Activated Protein Kinases
keywords: CaMKII; FasL; Ischemic preconditioning; Neuroprotection; PSD95; c-Jun; nNOS