title: Tetramethylpyrazine analogue CXC195 ameliorates cerebral ischemia-reperfusion injury by regulating endothelial nitric oxide synthase phosphorylation via PI3K/Akt signaling.
abstract: A novel tetramethylpyrazine derivative, CXC195, has been recently shown to protect against cerebral ischemia-reperfusion (I/R) injury. However, the detailed mechanisms underlying the neuroprotection of CXC195 are still unclear. The aim of the present study was to investigate the effects of CXC195 on the phosphorylation of endothelial nitric oxide synthase (eNOS) in response to cerebral I/R and to determine whether phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway might be involved. An in vitro model of oxygen glucose deprivation (OGD) which was performed on primary cultured human aortic endothelial cells (HAECs) and an in vivo middle cerebral artery occlusion (MCAO) model that was performed on Wistar rats were used in this study. CXC195 increased nitric oxide (NO) production and the phosphorylation but not the protein level of eNOS in HAECs subjected to 1 h OGD followed by reperfusion. In addition, CXC195 increased the phosphorylation of Akt; inhibition of PI3K/Akt pathway by a specific inhibitor, wortmannin, suppressed CXC195-induced NO release in HAECs. Consistently, CXC195 treatment significantly restored the phosphorylations of eNOS and Akt in the cortical penumbra of rats subjected to 2 h MCAO followed by reperfusion. Moreover, wortmannin abolished CXC195-induced eNOS phosphorylation and neuroprotection as evidenced by a reversal of the reduction in infarct volume and neurobehavioral outcomes. In conclusion, CXC195 induced phosphorylation of eNOS by activation of PI3K/Akt signaling under pathological cerebral I/R conditions, which provided a novel explanation for the neuroprotective effect of CXC195.
authors.affiliation: Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Wenhua West Road 107#, Jinan, 250012, Shandong, People's Republic of China.
authors.forename: Shi
authors.initials: S
authors.lastname: Yan
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Xinbing
authors.initials: X
authors.lastname: Wei
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.forename: Lingjun
authors.initials: L
authors.lastname: Kong
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhang
authors.forename: Huiqing
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C552200:CXC 195; D010879:Piperazines; D011719:Pyrazines; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C017953:tetramethylpyrazine