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Research ArticleNEUROPHARMACOLOGY

Naloxone Protects Rat Dopaminergic Neurons against Inflammatory Damage through Inhibition of Microglia Activation and Superoxide Generation

Bin Liu, Lina Du and Jau-Shyong Hong
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 607-617;
Bin Liu
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Lina Du
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Jau-Shyong Hong
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Abstract

Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is a hallmark of Parkinson's disease and inflammation and oxidative stress are closely associated with the pathogenesis of degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, resident immune cells of the brain, to release proinflammatory and neurotoxic factors tumor necrosis factor-α, interleukin-1β, nitric oxide, and superoxide and subsequently caused damage to midbrain neurons, including dopaminergic neurons. The LPS-induced degeneration of the midbrain neurons was significantly reduced by cotreatment with naloxone, an opioid receptor antagonist. This study focused on understanding the mechanism of action for the protective effect of naloxone on dopaminergic neurons because of relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency. Naloxone inhibited LPS-induced activation of microglia and release of proinflammatory factors, and inhibition of microglia generation of superoxide free radical best correlated with the neuroprotective effect of naloxone isomers. To further delineate the site of action, naloxone was found to partially inhibit the binding of [3H]LPS to cell membranes, whereas it failed to prevent damage to dopaminergic neurons by peroxynitrite, a product of nitric oxide and superoxide. These results suggest that naloxone at least in part interferes with the binding of LPS to cell membranes to inhibit microglia activation and protect dopaminergic neurons as well as other neurons in the midbrain cultures from inflammatory damage.

Footnotes

  • Send reprint requests to: Bin Liu, M.D., Ph.D., National Institute of Environmental Health Sciences, Laboratory of Pharmacology and Chemistry, MD: F1-01, P.O. Box 12233, Research Triangle Park, NC 27709. E-mail: liu3{at}niehs.nih.gov

  • ↵1 This study was supported in part of by National Institute of Environmental Health Sciences/National Institutes of Health intramural research fund.

  • ↵2 B.L. is a recipient of the National Institutes of Health Research Excellence Award.

  • ↵3 L.D. is on leave from Shanghai Medical University, State Key Laboratory of Medical Neurobiology, Shanghai, China.

  • Abbreviations:
    NO
    nitric oxide
    TNF-α
    tumor necrosis factor-α
    IL-1β
    interleukin-1β
    LPS
    lipopolysaccharide
    FBS
    fetal bovine serum
    OX-42
    anti-CR3 complement receptor antibody
    Neu-N
    neuron-specific nuclear protein
    MAP-2
    microtubule-associated protein-2
    GFAP
    glial fibrillary acidic protein
    TH
    tyrosine hydroxylase
    SOD
    superoxide dismutase
    ELISA
    enzyme-linked immunosorbent assay
    HBSS
    Hanks' balanced salt solution
    PMA
    phorbol-12-myristate-13-acetate
    • Received October 5, 1999.
    • Accepted January 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleNEUROPHARMACOLOGY

Naloxone Protects Rat Dopaminergic Neurons against Inflammatory Damage through Inhibition of Microglia Activation and Superoxide Generation

Bin Liu, Lina Du and Jau-Shyong Hong
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 607-617;

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Research ArticleNEUROPHARMACOLOGY

Naloxone Protects Rat Dopaminergic Neurons against Inflammatory Damage through Inhibition of Microglia Activation and Superoxide Generation

Bin Liu, Lina Du and Jau-Shyong Hong
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 607-617;
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