A cytokine mixture of GM-CSF and IL-3 that induces a neuroprotective phenotype of microglia leading to amelioration of (6-OHDA)-induced Parkinsonism of rats

Authors

  • Mohammed Emamussalehin Choudhury,

    1. Department of Therapeutic Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
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  • Kana Sugimoto,

    1. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
    2. Department of Basic and Clinical Neuroscience, Ehime Proteo-Medicine Research Center, Ehime University, Toon, Ehime, Japan
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  • Madoka Kubo,

    1. Department of Therapeutic Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
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  • Masahiro Nagai,

    1. Department of Therapeutic Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
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  • Masahiro Nomoto,

    1. Department of Therapeutic Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
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  • Hisaaki Takahashi,

    1. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
    2. Department of Basic and Clinical Neuroscience, Ehime Proteo-Medicine Research Center, Ehime University, Toon, Ehime, Japan
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  • Hajime Yano,

    1. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
    2. Department of Basic and Clinical Neuroscience, Ehime Proteo-Medicine Research Center, Ehime University, Toon, Ehime, Japan
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  • Junya Tanaka

    1. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan
    2. Department of Basic and Clinical Neuroscience, Ehime Proteo-Medicine Research Center, Ehime University, Toon, Ehime, Japan
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Junya Tanaka, M.D., Ph.D., Department of Basic and Clinical Neuroscience, Ehime Proteo-Medicine Research Center, Ehime University Toon, Ehime 791-0295, Japan. Tel: +81-89-960-5241; Fax: +81-89-960-5242; E-mail: jtanaka@m.ehime-u.ac.jp

Abstract

Dopamine (DA) agonists are widely used as primary treatments for Parkinson's disease. However, they do not prevent progressive degeneration of dopaminergic neurons, the central pathology of the disease. In this study, we found that subcutaneous injection of a cytokine mixture containing granulocyte macrophage colony-stimulating factor and interleukin-3 (IL-3) markedly suppressed dopaminergic neurodegeneration in 6-hydroxydopamine-lesioned rats, an animal model of Parkinson's disease. The cytokine mixture suppressed the decrease of DA content in the striatum, and ameliorated motor function in the lesioned rats. In response to the cytokine injection, dopaminergic neurons in the substantia nigra pars compacta increased expression of the antiapoptotic protein Bcl-xL. Microglial activation in the pars compacta was evident in both the saline- and cytokine-injected rats. However, the cytokine mixture suppressed expression of the proinflammatory cytokines IL-1β and tumor necrosis factors α, and upregulated the neuroprotective factors insulin-like growth factor-1 and hepatocyte growth factor. Similar responses were observed in cultured microglia. Detailed morphometric analyses revealed that NG2 proteoglycan-expressing glial cells increased in the cytokine-injected rats, while astrocytic activation with increased expression of antioxidative factors was evident only in the saline-injected rats. Thus, the present findings show that the cytokine mixture was markedly effective in suppressing neurodegeneration. Its neuroprotective effects may be mediated by increased expression of Bcl-xL in dopaminergic neurons, and the activation of beneficial actions of microglia that promote neuronal survival. Furthermore, this cytokine mixture may have indirect actions on NG2 proteoglycan-expressing glia, whose role may be implicated in neuronal survival.

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