Chotosan Enhances Macrophage Colony-Stimulating Factor mRNA Expression in the Ischemic Rat Brain and C6Bu-1 Glioma Cells

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  • Obi Ryosuke
    Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama
  • Tohda Michihisa
    Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama
  • Zhao Qi
    Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama 21st Century COE program, University of Toyama
  • Obi Nobuko
    Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 21st Century COE program, University of Toyama
  • Hori Hitomi
    Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama
  • Murakami Yukihisa
    Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama
  • Goto Hirozo
    Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 21st Century COE program, University of Toyama
  • Shimada Yutaka
    Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama 21st Century COE program, University of Toyama
  • Ochiai Hiroshi
    Department of Human Science, Faculty of Medicine, University of Toyama 21st Century COE program, University of Toyama
  • Matsumoto Kinzo
    Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama 21st Century COE program, University of Toyama

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Macrophage colony stimulating factor (M-CSF) is a cytokine which has been recently reported to have a neuroprotective effect on ischemic rat brain. In this study, we investigated the effect of chotosan, an oriental medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on M-CSF gene expression in rats with permanent occlusion of bilateral common carotid arteries (P2VO) in vivo and in a C6Bu-1 glioma cell line in vitro. The expression level of M-CSF mRNA in the cerebral cortices of P2VO rats was significantly higher than that in the cerebral cortices of sham-operated animals. Repeated treatment of P2VO rats with chotosan (75 mg/kg per day) for 4 d after P2VO significantly increased the expression level of M-CSF mRNA in the cortex but it had no effect on the expression of β-actin, granulocyte colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF) mRNAs. Moreover, the present in vitro studies revealed that chotosan treatment (10—100 μg/ml) of C6Bu-1 glioma cells dose-dependently enhanced M-CSF mRNA expression without affecting the expression of G-CSF, GM-CSF, and inducible nitric oxide synthase mRNAs. The effect of chotosan was reversed by Ro 31-8220 (1 μM), a selective protein kinase C (PKC) inhibitor, but not by H-89 (10 μM), a selective protein kinase A (PKA) inhibitor. These findings suggest that the upregulatory effect of chotosan on M-CSF mRNA expression involves PKC and may play an important role in the anti-vascular dementia action of this formula.

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