title: Granulocyte-colony stimulating factor in combination with stem cell factor confers greater neuroprotection after hypoxic-ischemic brain damage in the neonatal rats than a solitary treatment.
abstract: Neonatal hypoxia-ischemia (HI) is a devastating condition resulting in neuronal cell death and often culminates in neurological deficits. Granulocyte-colony stimulating factor (G-CSF) has been shown to have neuroprotective activity via inhibition of apoptosis and inflammation in various stroke models. Stem cell factor (SCF) regulates hematopoietic stem cells in the bone marrow and has been reported to have neuroprotective properties in an experimental ischemic stroke model. In this study we aim to determine the protective effects of G-CSF in combination with SCF treatment after experimental HI. Seven-day old Sprague-Dawley rats were subjected to unilateral carotid artery ligation followed by 2.5 hours of hypoxia. Animals were randomly assigned to five groups: Sham (n=8), Vehicle (n=8), HI with G-CSF treatment (n=9), HI with SCF treatment (n=9) and HI with G-CSF+SCF treatment (coadministration group; n=10). G-CSF (50 µg/kg), SCF (50 µg/kg) and G-CSF+SCF (50 µg/kg) were administered intraperitoneally 1 hour post HI followed by daily injection for 4 consecutive days (five total injections). Animals were euthanized 14 days after HI for neurological testing. Additionally assessment of brain, heart, liver, spleen and kidney atrophy was performed. Both G-CSF and G-CSF+SCF treatments improved body growth and decreased brain atrophy at 14 days post HI. No significant differences were found in the peripheral organ weights between groups. Finally, the G-CSF+SCF coadministration group showed significant improvement in neurological function. Our data suggest that administration of G-CSF in combination with SCF not only prevented brain atrophy but also significantly improved neurological function.
authors.affiliation: Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, California, USA.
authors.forename: Desislava
authors.initials: D
authors.lastname: Doycheva
authors.forename: Gary
authors.initials: G
authors.lastname: Shih
authors.forename: Hank
authors.initials: H
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Applegate
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019089:Stem Cell Factor / Q000008:administration & dosage*
chemical_list: D018696:Neuroprotective Agents; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor
keywords: Granulocyte-colony stimulating factor (G-CSF); Hypoxia-ischemia (HI); Neurological outcome; Stem cell factor (SCF)
references.citation: Neuroscience. 2006 Dec 28;143(4):965-74
references.pmid: 17084035
references.citation: CMAJ. 2006 Mar 28;174(7):927-33
references.pmid: 16517764
references.citation: Exp Neurol. 2002 Oct;177(2):443-52
references.pmid: 12429190
references.citation: Exp Hematol. 1991 Mar;19(3):226-31
references.pmid: 1704845
references.citation: Exp Neurol. 2007 Apr;204(2):569-73
references.pmid: 17307165
references.citation: Brain Res. 2007 May 11;1145:227-38
references.pmid: 17359943
references.citation: J Cereb Blood Flow Metab. 2003 Jun;23(6):709-17
references.pmid: 12796719
references.citation: Exp Neurol. 2004 Apr;186(2):134-44
references.pmid: 15026252
references.citation: Transfusion. 2001 Feb;41(2):184-9
references.pmid: 11239220
references.citation: Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):751-7
references.pmid: 16439710
references.citation: Stroke. 2007 Sep;38(9):2584-91
references.pmid: 17656664
references.citation: Eur J Pharmacol. 2004 Jan 19;484(1):65-74
references.pmid: 14729383
references.citation: Behav Brain Res. 2005 Nov 30;165(1):80-90
references.pmid: 16140403
references.citation: Acta Paediatr. 2004 Dec;93(12):1635-9
references.pmid: 15841773
references.citation: J Neuropathol Exp Neurol. 2005 Sep;64(9):763-9
references.pmid: 16141785
references.citation: Brain Res. 2006 Jul 7;1098(1):161-9
references.pmid: 16814750
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1808-13
references.pmid: 8700840
references.citation: Brain Res. 2005 May 31;1045(1-2):22-30
references.pmid: 15910759
references.citation: Stroke. 2007 Oct;38(10):2804-11
references.pmid: 17761920
references.citation: Int J Clin Lab Res. 1993;23(2):70-7
references.pmid: 7686057
references.citation: J Leukoc Biol. 1995 Jul;58(1):14-22
references.pmid: 7542304
references.citation: Onkologie. 2003 Feb;26(1):73-9
references.pmid: 12624522
references.citation: J Clin Invest. 2005 Aug;115(8):2083-98
references.pmid: 16007267
references.citation: Blood. 2000 Nov 15;96(10):3422-30
references.pmid: 11071637
references.citation: Yonsei Med J. 2008 Oct 31;49(5):836-42
references.pmid: 18972605
references.citation: Ann N Y Acad Sci. 1997 Dec 19;835:234-49
references.pmid: 9616778
references.citation: Stroke. 1995 Apr;26(4):627-34; discussion 635
references.pmid: 7709410
references.citation: J Biol Chem. 1997 Oct 3;272(40):25184-9
references.pmid: 9312131
references.citation: Acta Neurochir Suppl. 2011;111:265-9
references.pmid: 21725766
references.citation: Ment Retard Dev Disabil Res Rev. 2001;7(1):56-64
references.pmid: 11241883
references.citation: Nat Med. 2001 Apr;7(4):430-6
references.pmid: 11283669
references.citation: Exp Neurol. 1988 Dec;102(3):318-24
references.pmid: 3197789
references.citation: Circulation. 2004 Sep 28;110(13):1847-54
references.pmid: 15381647
references.citation: Stroke. 2006 Dec;37(12):2979-83
references.pmid: 17082474
references.citation: Brain. 2008 Dec;131(Pt 12):3335-47
references.pmid: 18835867
references.citation: J Cereb Blood Flow Metab. 2006 Mar;26(3):402-13
references.pmid: 16049425
references.citation: Blood. 2008 Jun 15;111(12):5544-52
references.pmid: 18268092
references.citation: Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):296-301
references.pmid: 15569821
references.citation: Blood. 2002 Aug 1;100(3):869-78
references.pmid: 12130497
references.citation: Ment Retard Dev Disabil Res Rev. 2002;8(4):241-8
references.pmid: 12454900
references.citation: Prog Growth Factor Res. 1991;3(4):235-42
references.pmid: 1725859
references.citation: Stroke. 2003 Mar;34(3):745-51
references.pmid: 12624302
references.citation: Ann Neurol. 1981 Feb;9(2):131-41
references.pmid: 7235629
references.citation: Physiol Res. 2005;54(4):357-62
references.pmid: 15588150
references.citation: Brain Res. 2007 Mar 9;1136(1):200-7
references.pmid: 17210148
references.citation: Eur J Pharmacol. 2003 Jan 5;458(3):327-8
references.pmid: 12504790
references.citation: Blood. 1994 Apr 15;83(8):2145-52
references.pmid: 7512842
references.citation: Pediatr Res. 1997 Nov;42(5):678-83
references.pmid: 9357943
references.citation: Intensive Care Med. 2010 Sep;36(9):1602-8
references.pmid: 20461500
references.citation: Pediatr Res. 1990 Apr;27(4 Pt 1):332-6
references.pmid: 2342827
references.citation: Neurol Res. 2009 Mar;31(2):167-72
references.pmid: 19298757
references.citation: Biol Neonate. 1994;66(4):205-13
references.pmid: 7865635
references.citation: Ann Hematol. 2003 Apr;82(4):207-13
references.pmid: 12707722
references.citation: Semin Fetal Neonatal Med. 2008 Dec;13(6):424-31
references.pmid: 18501692
references.citation: Stroke. 2010 May;41(5):1027-31
references.pmid: 20360546
references.citation: Circulation. 2006 Feb 7;113(5):701-10
references.pmid: 16461843
references.citation: Tex Heart Inst J. 2005;32(3):339-47
references.pmid: 16392214
references.citation: Behav Brain Res. 2005 Feb 10;157(1):157-65
references.pmid: 15617782
references.citation: N Engl J Med. 2004 Nov 4;351(19):1985-95
references.pmid: 15525724