title: Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury.
abstract: Granulocyte-colony stimulating factor (G-CSF) protects brain from ischemic/reperfusion (I/R) injury, and inhibition of nitric oxide (NO) synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF) and neurological deficit. Endothelin-1 (ET-1) microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia) which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion) within the striatal region. Regional NO concentration increased rapidly (NO surge) during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-N(G)-Nitroarginine Methyl Ester (L-NAME) significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury.
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Zhongyang Road, Hualien City 970, Taiwan.
authors.forename: Hock-Kean
authors.initials: HK
authors.lastname: Liew
authors.affiliation: Institute of Pharmacology and Toxicology, Tzu Chi University, No. 701, Section 3, Zhongyang Road, Hualien City 970, Taiwan.
authors.forename: Jon-Son
authors.initials: JS
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 110, Taiwan.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Medical Research, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Zhongyang Road, Hualien City 970, Taiwan ; Institute of Medical Sciences, Tzu Chi University, No. 701, Section 3, Zhongyang Road, Hualien City 970, Taiwan.
authors.forename: Cheng-Yoong
authors.initials: CY
authors.lastname: Pang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: D018696:Neuroprotective Agents; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D019331:NG-Nitroarginine Methyl Ester