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Research ArticleNEUROPHARMACOLOGY

Dextromethorphan Protects Dopaminergic Neurons against Inflammation-Mediated Degeneration through Inhibition of Microglial Activation

Yuxin Liu, Liya Qin, Guorong Li, Wei Zhang, Lijia An, Bin Liu and Jau-Shyong Hong
Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 212-218; DOI: https://doi.org/10.1124/jpet.102.043166
Yuxin Liu
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Liya Qin
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Guorong Li
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Wei Zhang
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Lijia An
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Bin Liu
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Jau-Shyong Hong
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Abstract

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors, including cytokines, reactive oxygen intermediates, nitric oxide, and eicosanoids that impact on neurons to induce neurodegeneration. Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases. In this study, we report that dextromethorphan (DM), an ingredient widely used in antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through inhibition of microglial activation. Pretreatment (30 min) of rat mesencephalic neuron-glia cultures with DM (1–10 μM) reduced, in a dose-dependent manner, the microglia-mediated degeneration of dopaminergic neurons induced by lipopolysaccharide (LPS, 10 ng/ml). Significant neuroprotection by DM was also evident when DM was applied to cultures up to 60 min after the addition of LPS. The neuroprotective effect of DM was attributed to inhibition of LPS-stimulated microglial activation because DM significantly inhibited the LPS-induced production of tumor necrosis factor-α, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium- or β-amyloid peptide (1–42)-induced dopaminergic neurotoxicity in neuron-enriched cultures. In addition, because LPS did not produce any significant increase in the release of excitatory amino acids from neuron-glia cultures andN-methyl-d-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated throughN-methyl-d-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease.

Footnotes

  • DOI: 10.1124/jpet.102.043166

  • Abbreviations:
    PD
    Parkinson's disease
    LPS
    lipopolysaccharide
    TNFα
    tumor necrosis factor-α
    IL
    interleukin
    NO
    nitric oxide
    MPP+
    1-methyl-4-phenylpyridinium
    DA
    dopamine
    TH
    tyrosine hydroxylase
    ir
    immunoreactive
    SOD
    superoxide dismutase
    HBSS
    Hanks' balanced salt solution
    XO
    xanthine oxidase
    NMDA
    N-methyl-d-aspartate
    • Received August 12, 2002.
    • Accepted December 9, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 305 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 1
1 Apr 2003
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Research ArticleNEUROPHARMACOLOGY

Dextromethorphan Protects Dopaminergic Neurons against Inflammation-Mediated Degeneration through Inhibition of Microglial Activation

Yuxin Liu, Liya Qin, Guorong Li, Wei Zhang, Lijia An, Bin Liu and Jau-Shyong Hong
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 212-218; DOI: https://doi.org/10.1124/jpet.102.043166

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Research ArticleNEUROPHARMACOLOGY

Dextromethorphan Protects Dopaminergic Neurons against Inflammation-Mediated Degeneration through Inhibition of Microglial Activation

Yuxin Liu, Liya Qin, Guorong Li, Wei Zhang, Lijia An, Bin Liu and Jau-Shyong Hong
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 212-218; DOI: https://doi.org/10.1124/jpet.102.043166
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