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Time-dependent effect of combination therapy with erythropoietin and granulocyte colony-stimulating factor in a mouse model of hypoxic-ischemic brain injury

 Ji Hea Yu  ;  Jung Hwa Seo  ;  Jong Eun Lee  ;  Ji Hoe Heo  ;  Sung-Rae Cho 
 NEUROSCIENCE BULLETIN, Vol.30(1) : 107-117, 2014 
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Animals ; Brain/drug effects* ; Disease Models, Animal ; Drug Therapy, Combination ; Erythropoietin/therapeutic use* ; Granulocyte Colony-Stimulating Factor/therapeutic use* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Ischemia, Brain/drug therapy* ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Neurogenesis/drug effects ; Neuroprotective Agents/therapeutic use*
erythropoietin ; granulocyte colonystimulating factor ; hypoxia-inducible factor-1 ; hypoxicischemic brain injury
Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are likely to play broad roles in the brain. We investigated the effects of combination therapy with EPO and G-CSF in hypoxic-ischemic brain injury during the acute, subacute, and chronic phases. A total of 79 C57BL/6 mice with hypoxic-ischemic brain injury were randomly assigned acute (days 1-5), subacute (days 11-15) and chronic (days 28-32) groups. All of them were treated with G-CSF (250 μg/kg) and EPO (5000 U/kg) or saline daily for 5 consecutive days. Behavioral assessments and immunohistochemistry for angiogenesis, neurogenesis, and astrogliosis were performed with an 8-week follow-up. Hypoxia-inducible factor-1 (HIF-1) was also measured by Western blot analysis. The results showed that the combination therapy with EPO and G-CSF in the acute phase significantly improved rotarod performance and forelimb-use symmetry compared to the other groups, while subacute EPO and G-CSF therapy exhibited a modest improvement compared with the chronic saline controls. The acute treatment significantly increased the density of CD31(+) (PECAM-1) and α-smooth muscle actin(+) vessels in the frontal cortex and striatum, increased BrdU(+)/PSA-NCAM(+) neurogenesis in the subventricular zone, and decreased astroglial density in the striatum. Furthermore, acute treatment significantly increased the HIF-1 expression in the cytosol and nucleus, whereas chronic treatment did not change the HIF-1 expression, consistent with the behavioral outcomes. These results indicate that the induction of HIF-1 expression by combination therapy with EPO and G-CSF synergistically enhances not only behavioral function but also neurogenesis and angiogenesis while decreasing the astroglial response in a time-dependent manner.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Rehabilitation Medicine (재활의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Seo, Jung Hwa(서정화)
Yu, Ji Hea(유지혜)
Lee, Jong Eun(이종은) ORCID logo https://orcid.org/0000-0001-6203-7413
Cho, Sung-Rae(조성래) ORCID logo https://orcid.org/0000-0003-1429-2684
Heo, Ji Hoe(허지회) ORCID logo https://orcid.org/0000-0001-9898-3321
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