Naloxone Reversal of Ischemic Arrhythmia Is Stereospecific and Suggests Role of Endogenous Opioid Peptides in Ischemic Heart Disease

Kan, Mee-Nin; Chen, Y. T.; Lee, A. Y. S.

doi:10.3181/00379727-200-43464

Cited by 11 publications

(5 citation statements)

References 4 publications

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“…For potential therapeutic purposes, naloxone has been tested in animal models and clinical trials to treat a wide range of disease conditions, including drug abuse, alcohol addiction, eating disorder, spinal cord injury, shock, and cerebral and cardiac ischemia (Hosobuchi et al, 1982;Fallis et al, 1983;Holaday and Malcolm, 1986;de Zwaan and Mitchell, 1992;Kan et al, 1992;Ward et al, 1999;Napolitano, 2000;Seidl, 2000;Anton, 2001;Chen et al, 2001). Although the efficacy of naloxone in treating drug abuse is clearly related to its activity as an opioid antagonist, the exact mechanism of action responsible for the efficacy of naloxone in other cases remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…During the past twenty years, naloxone has been tested for beneficial effects in a variety of experimental disease models and patients of septic shock,76–78 injuries to spinal cord or brain,79,80 myocardiac and cerebral stroke,81–85 and Alzheimer's disease 86. Although the use of naloxone is more encouraging in some disease conditions, such as ischemia,81–85 conflicting results have been obtained in others. For example, interest in the beneficial effect during the treatment of patients with Alzheimer's disease was high in the early 1980s 86–89.…”

Section: Opioids Brain Inflammation and Neurodegenerationmentioning

confidence: 99%

Role of Nitric Oxide in Inflammation‐Mediated Neurodegeneration

Liu

Gao

Wang

et al. 2002

Annals of the New York Academy of Sciences

399

283

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Increasing evidence has suggested that inflammation in the brain is closely associated with the pathogenesis of several degenerative neurologic disorders, including Parkinson's disease, Alzheimer's diseases, multiple sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of brain inflammation is the activation of glial cells, especially that of microglia that produce a variety of proinflammatory and neurotoxic factors, including cytokines, fatty acid metabolites, free radicals--such as nitric oxide (NO) and superoxide. Excessive production of NO, as a consequence of nitric oxide synthase induction in activated glia, has been attributed to participate in neurodegeneration. Using primary mixed neuron-glia cultures and glia-enriched cultures prepared from embryonic rodent brain tissues, we have systemically studied the relationship between the production of NO and neurodegeneration in response to stimulation by the inflammagen lipopolysaccharide. This review summarizes our recent findings on the kinetics of NO generation, the relative contribution of microglia and astrocytes to NO accumulation, the relationship between NO production and neurodegeneration, and points of intervention along the pathways associated with NO generation to achieve neuroprotection. We also describe our results relating to the effect of several opioid-related agents on microglial activation and neuroprotection. Among these agents, the opioid receptor antagonist naloxone, especially its non-opioid enantiomer (+)-naloxone, promises to be of potential therapeutic value for the treatment of inflammation-related diseases.

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“…Naloxone is a structural analog of morphine and an effective antagonist of the classic opioid receptors that are widely expressed on cells of the central and peripheral nervous systems (12). Administration of naloxone has been demonstrated to be beneficial in the treatment of experimental models of stroke, myocardial and brain ischemia, brain trauma, spinal cord injuries and septic shock (13)(14)(15). Naloxone has been demonstrated to attenuate the degeneration of dopaminergic neurons by inhibition of β-amyloid peptide(1-42)-induced microglial activation and degeneration of cortical and mesencephalic neurons, suggesting that naloxone may have potential therapeutic efficacy for the treatment of Parkinson's and Alzheimer's disease (16,17).…”

Section: Introductionmentioning

confidence: 99%

HSP60 is involved in the neuroprotective effects of naloxone

Cheng

Hou

et al. 2014

Molecular Medicine Reports

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Heat shock protein (HSP)60 is primarily a mitochondrial protein. Previous experiments have found that changes in the location of intracellular HSP60 have been associated with apoptosis. Extracellular HSP60 mediates apoptosis via its ligand, Toll‑like receptor (TLR)-4. TLR-4 is an important factor expressed on microglia, with a central role in generating neuroimmune responses in the pathogenesis of neurodegenerative disorders. Naloxone is a highly effective nonselective opioid receptor antagonist, and has been reported to be pharmacologically beneficial for the treatment of brain diseases through inhibiting microglia activation. However, the mechanisms underlying these beneficial effects of naloxone remain poorly understood. The present study aimed to investigate the role of HSP60 in the neuroprotective effects of naloxone on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 murine microglial cells and the possible signaling pathways involved. The results demonstrated that naloxone significantly inhibited the expression and release of HSP60 in BV2 cells. The expression levels of heat shock factor (HSF)-1 were upregulated in LPS‑activated BV2 cells, which indicated that the increased expression of HSP60 was driven by HSF-1 activation. However, increased HSF‑1 levels may be downregulated by naloxone. The levels of TLR‑4 were elevated in activated BV2 cells, and then inhibited by naloxone. Activation of TLR‑4 is characterized by activation of nuclear factor-κB (NF-κB) followed by the production of various proinflammatory and neurotoxic factors. Data from the present study demonstrated that naloxone reduced the expression levels of NF-κB and its upstream protein caspase‑3, and reduced the LPS-induced production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor α, interleukin-1β and interleukin-6 in BV2 microglia. In light of this data, it was concluded that naloxone may exert its neuroprotective and anti‑inflammatory effects by inhibiting microglia activation through a HSP60‑TLR‑4‑NF‑κB signaling pathway.

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Naloxone Reversal of Ischemic Arrhythmia Is Stereospecific and Suggests Role of Endogenous Opioid Peptides in Ischemic Heart Disease

Cited by 11 publications

References 4 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

Role of Nitric Oxide in Inflammation‐Mediated Neurodegeneration

HSP60 is involved in the neuroprotective effects of naloxone

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