title: Mechanisms of neuroprotection from hypoxia-ischemia (HI) brain injury by up-regulation of cytoglobin (CYGB) in a neonatal rat model.
abstract: This study was designed to investigate the expression profile of CYGB, its potential neuroprotective function, and underlying molecular mechanisms using a model of neonatal hypoxia-ischemia (HI) brain injury. Cygb mRNA and protein expression were evaluated within the first 36 h after the HI model was induced using RT-PCR and Western blotting. Cygb mRNA expression was increased at 18 h in a time-dependent manner, and its level of protein expression increased progressively in 24 h. To verify the neuroprotective effect of CYGB, a gene transfection technique was employed. Cygb cDNA and shRNA delivery adenovirus systems were established (Cygb-cDNA-ADV and Cygb-shRNA-ADV, respectively) and injected into the brains of 3-day-old rats 4 days before they were induced with HI treatment. Rats from different groups were euthanized 24 h post-HI, and brain samples were harvested. 2,3,5-Triphenyltetrazolium chloride, TUNEL, and Nissl staining indicated that an up-regulation of CYGB resulted in reduced acute brain injury. The superoxide dismutase level was found to be dependent on expression of CYGB. The Morris water maze test in 28-day-old rats demonstrated that CYGB expression was associated with improvement of long term cognitive impairment. Studies also demonstrated that CYGB can up-regulate mRNA and protein levels of VEGF and increase both the density and diameter of the microvessels but inhibits activation of caspase-2 and -3. Thus, this is the first in vivo study focusing on the neuroprotective role of CYGB. The reduction of neonatal HI injury by CYGB may be due in part to antioxidant and antiapoptotic mechanisms and by promoting angiogenesis.
authors.affiliation: Department of Pediatrics, the Second Affiliated Hospital, Shantou University Medical College, North Section of Dong-xia Road, Shantou, Guangdong 515041, China.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Tian
authors.forename: Han-Hua
authors.initials: HH
authors.lastname: Yang
authors.forename: Dan-Ping
authors.initials: DP
authors.lastname: Xiao
authors.forename: Yue-Jun
authors.initials: YJ
authors.lastname: Huang
authors.forename: Gu-Yu
authors.initials: GY
authors.lastname: He
authors.forename: Hai-Ran
authors.initials: HR
authors.lastname: Ma
authors.forename: Fang
authors.initials: F
authors.lastname: Xia
authors.forename: Xue-Chuan
authors.initials: XC
authors.lastname: Shi
mesh_terms: D000208:Acute Disease; D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D000078842:Cytoglobin; D005260:Female; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D018782:Maze Learning; D018919:Neovascularization, Physiologic / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014161:Transduction, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000975:Antioxidants; C000627268:Cygb protein, rat; D000078842:Cytoglobin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D005914:Globins; C490359:Casp2 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D003546:Cysteine Endopeptidases
keywords: Angiogenesis; Apoptosis; Cytoglobin; Hypoxia; Ischemia; Mechanisms; Neuroprotection