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Naloxone Protects Rat Dopaminergic Neurons against Inflammatory Damage through Inhibition of Microglia Activation and Superoxide Generation
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-alpha, interleukin-1beta, 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 [(3)H]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.
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“Alternative drugs with anti-inflammatory properties, including dexamethasone, minocycline, naloxone, are going to be or have already been tested in preclinical and clinical trials.560–562”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [562]
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Metadata
- Authors
- Liu, B., Du, L., & Hong, J.-S.
- Affiliations
- National Institutes of Health (US)
- National Institute of Environmental Health Sciences (US)
- Corresponding author
- Liu, Bin
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2000-04
- Volume
- 293
- Issue
- 2
- Pages
- 607-617
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1891696008
- Cited by
- 347
- References
- 43
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 11 · 2022: 11 · 2021: 10 · 2020: 5 · 2019: 2 · 2018: 7 · 2017: 12 · 2016: 10 · 2015: 16 · 2014: 11 · 2013: 13 · 2012: 26
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- naloxone, dopaminergic neurons, Parkinson's disease, microglial activation, lipopolysaccharide, neuroinflammation, oxidative stress, superoxide, neuroprotection, substantia nigra, opioid antagonists, peroxynitrite, nitric oxide, inflammatory cytokines
- MeSH terms
- Animals, Cells, Cultured, Dopamine, Immunohistochemistry, Inflammation, Interleukin-1, Lipopolysaccharides, Mesencephalon, Naloxone, Narcotic Antagonists, Neurons, Nitrates, Nitrites, Rats, Inbred F344, Stereoisomerism, Substantia Nigra, Superoxides, Tumor Necrosis Factor-alpha, Tyrosine 3-Monooxygenase, Oxidants, Microglia, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Rats
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