Naloxone inhibits superoxide release from human neutrophils

Simpkins, Cuthbert O.; Ives, Nadine; Tate, E.; Johnson, Mark E.

doi:10.1016/0024-3205(85)90076-1

Cited by 42 publications

(15 citation statements)

References 7 publications

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“…More interestingly, generation of ROS may be an upstream event that participates in the production of additional mediators such as TNF␣, as recently demonstrated by Sanlioglu et al (2001). Therefore, it is plausible to speculate that inhibition of superoxide generation by naloxone and related compounds in either central nervous system (Chang et al, 2000;Liu et al, 2000a; this study) or peripheral system (Simpkins et al, 1985) may be part of the mechanisms of action responsible for the observed protective effects.…”

Section: Discussionsupporting

confidence: 58%

Inhibition by Naloxone Stereoisomers of β-Amyloid Peptide (1–42)-induced Superoxide Production in Microglia and Degeneration of Cortical and Mesencephalic Neurons

Liu¹,

Qin²,

Wilson³

et al. 2002

J Pharmacol Exp Ther

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Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, attenuated the inflammation-mediated degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain. Recently we discovered that ␤-amyloid peptide A␤ (1-42) exhibited enhanced neurotoxicity toward both cortical and mesencephalic neurons through the activation of microglia and production of superoxide. The purpose of this study was to determine whether naloxone isomers had any effect on A␤ (1-42)-induced neurodegeneration. Pretreatment of either cortical or mesencephalic neuron-glia cultures with 1 to 10 M (Ϫ)-naloxone, prior to treatment for up to 11 days with 0.1 to 3 M A␤ (1-42), afforded significant neuroprotection as judged by neurotransmitter uptake, immunocytochemical analysis, and cell counting. More importantly, (ϩ)-naloxone, the ineffective enantiomer of (Ϫ)-naloxone in binding opioid receptors, was equally effective in affording neuroprotection. Mechanistically, inhibition of A␤ (1-42)-induced production of superoxide in microglia underlay the neuroprotective effect of naloxone stereoisomers. Moreover, neuroprotection and inhibition of A␤ (1-42)-induced superoxide production was also achieved with naloxone methiodide, a charged analog with quaternary amine, suggesting that the site of action for naloxone isomers is at the cell surface of microglia. These results demonstrated that naloxone isomers, through mechanisms unrelated to the opioid receptors, were capable of inhibiting A␤ (1-42)-induced microglial activation and degeneration of both cortical and mesencephalic neurons. Combined with our previous observations with inflammagen-induced neurodegeneration, naloxone analogs, especially (ϩ)-naloxone, may have potential therapeutic efficacy for the treatment of Alzheimer's and Parkinson's disease.

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Section: Discussionsupporting

confidence: 58%

Inhibition by Naloxone Stereoisomers of β-Amyloid Peptide (1–42)-induced Superoxide Production in Microglia and Degeneration of Cortical and Mesencephalic Neurons

Liu¹,

Qin²,

Wilson³

et al. 2002

J Pharmacol Exp Ther

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“…The inhibitory and neuroprotective profile of DM seems to be similar to that of naloxone stereoisomers. Naloxone is more effective in the inhibition of superoxide generation than TNF␣, NO, or IL-1␤ (Simpkins et al, 1985;Chang et al, 2000;Liu et al, 2000aLiu et al, , 2002b. The neuroprotective effect of naloxone has been observed in both the in vitro and in vivo models of inflammation-mediated neurodegeneration (Lu et al, 2000;Liu et al, 2000aLiu et al, ,b, 2002b).…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Qin²,

Li³

et al. 2003

J Pharmacol Exp Ther

313

385

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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 M) 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-␣, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium-or ␤-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 and N-methyl-D-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated through N-methyl-D-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease.

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“…Consequently, there is an urgent need to identify and understand the molecular mechanisms of morphine that function independently of the mu-opioid receptor, to prevent narcotic addiction resulting from treatment for these chronic inflammatory conditions. Recent studies have shown that morphine can work in both opioid receptor-dependent and -independent manners (11,(15)(16)(17)(18)(19). Further, our laboratory and others have found that naloxone and naltrexone, which are mu-opioid receptor antagonists, also show significant anti-inflammatory properties both in vitro and in vivo (20,21).…”

Section: P Arkinson's Disease (Pd)mentioning

confidence: 93%

Microglia-Mediated Neurotoxicity Is Inhibited by Morphine through an Opioid Receptor-Independent Reduction of NADPH Oxidase Activity

Tan

Wei

et al. 2007

The Journal of Immunology

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Recent studies have shown that morphine modulates the function of glia cells through both opioid receptor dependent and independent mechanisms. However, the mechanism by which morphine regulates neuronal disorders through the alteration of microglia activity remains unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that both l-morphine and its synthetic stereoenantiomer, d-morphine, an ineffective opioid receptor agonist, significantly reduced LPS- or 1-methyl-4-phenylpyridinium-induced dopaminergic neurotoxicity with similar efficacy, indicating a nonopioid receptor-mediated effect. In addition, using reconstituted neuron and glia cultures, subpicomolar concentrations of morphine were found to be neuroprotective only in the presence of microglia, and significantly inhibited the production of inflammatory mediators from LPS-stimulated microglia cells. Mechanistic studies showed that both l- and d- morphine failed to protect dopaminergic neurons in cultures from NADPH oxidase (PHOX) knockout mice and significantly reduced LPS-induced PHOX cytosolic subunit p47phox translocation to the cell membrane by inhibiting ERK phosphorylation. Taken together, our results demonstrate that morphine, even at subpicomolar concentrations, exerts potent anti-inflammatory and neuroprotective effects either through the inhibition of direct microglial activation by LPS or through the inhibition of reactive microgliosis elicited by 1-methyl-4-phenylpyridinium. Furthermore, our study reveals that inhibition of PHOX is a novel site of action for the mu-opioid receptor-independent effect of morphine.

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Naloxone inhibits superoxide release from human neutrophils

Cited by 42 publications

References 7 publications

Inhibition by Naloxone Stereoisomers of β-Amyloid Peptide (1–42)-induced Superoxide Production in Microglia and Degeneration of Cortical and Mesencephalic Neurons

Inhibition by Naloxone Stereoisomers of β-Amyloid Peptide (1–42)-induced Superoxide Production in Microglia and Degeneration of Cortical and Mesencephalic Neurons

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

Microglia-Mediated Neurotoxicity Is Inhibited by Morphine through an Opioid Receptor-Independent Reduction of NADPH Oxidase Activity

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