Time-dependent effect of combination therapy with erythropoietin and granulocyte colony-stimulating factor in a mouse model of hypoxic-ischemic brain injury |
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Authors: | Ji Hea Yu Jung Hwa Seo Jong Eun Lee Ji Hoe Heo Sung-Rae Cho |
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Affiliation: | 1. Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea 2. Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea 3. Graduate Program of Nano Science and Technology, Yonsei University, Seoul, Korea 4. Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea 5. Department of Neurology, Yonsei University College of Medicine, Seoul, Korea 6. Yonsei Stem Cell Center, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea 7. Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul, Korea
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Abstract: | Erythropoietin (EPO) and granulocyte colonystimulating 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 hypoxicischemic 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 (5 000 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+/PSANCAM+ 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 timedependent manner. |
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Keywords: | erythropoietin granulocyte colonystimulating factor hypoxia-inducible factor-1 hypoxicischemic brain injury |
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