title: Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice.
abstract: Cerebral ischemia induces the expression of several growth factors and cytokines, which protect neurons against ischemic insults. Recent studies showed that granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect through the signaling pathway for the antiapoptotic cascade. The current study was designed to assess the neuroprotective mechanisms of G-CSF in ischemia/reperfusion injury using bone marrow chimera mice known to express enhanced green fluorescent protein (EGFP). Mice were subjected to ischemia/reperfusion and divided into two groups: those treated with G-CSF (G-CSF group) and vehicle (control group) (n = 35 in each group). Immunohistochemistry and immunoblotting for antiapoptotic protein, nitrotyrosine, and inducible nitrate oxide synthase (iNOS) were performed. G-CSF significantly reduced stroke volume (34%, P < 0.006). G-CSF upregulated Stat3, pStat3, and Bcl-2 (P < 0.05), and suppressed iNOS and nitrotyrosine expression. In EGFP chimera mice, G-CSF decreased the migration of Iba-1/EGFP-positive bone marrow-derived monocytes/macrophages and increased intrinsic microglia/macrophages at ischemic penumbra (P < 0.05), suggesting that bone marrow-derived monocytes/macrophages are not involved in G-CSF-induced reduction of ischemic injury size. Our study indicated that G-CSF exerts a neuroprotective effect through the direct activation of antiapoptotic pathway, and suggested that G-CSF is important for expansion of the therapeutic time window in patients with cerebral ischemia.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Komine-Kobayashi
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Meizi
authors.initials: M
authors.lastname: Liu
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
authors.forename: Akimichi
authors.initials: A
authors.lastname: Osaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Takao
authors.initials: T
authors.lastname: Urabe
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000187:drug effects; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000187:drug effects; D015996:Survival Rate; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II