Morphinan Neuroprotection: New Insight into the Therapy of Neurodegeneration

Zhang, Wei; Hong, Jau–Shyong; Kim, Hyoung Chun; Zhang, Wanqin; Block, Michelle L.

doi:10.1615/critrevneurobiol.v16.i4.30

Cited by 10 publications

(8 citation statements)

References 94 publications

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“…Increasing evidence from both in vivo and in vitro studies suggest that morphinans possess important immunomodulatory potential (62). Morphinans are a group of compounds structurally similar to morphine, but lacking the E-ring found in the naturally occurring opioids, as well as the 6-OH and the 7,8-double bond.…”

Section: Discussionmentioning

confidence: 99%

“…Our studies and those of others have shown that these compounds work at very low concentrations, to inhibit both cellular activation and microglial cell-mediated neurotoxicity. More importantly, the dextrorotatory form of this compound, which has no affinity or effect on the mi-opioid receptors and therefore does not cause addiction, is equally if not more effective than its l form in mediating anti-inflammatory effects on microglia (62). Given the effectiveness of these compounds at such low concentrations and the broad spectrum of activity in inhibiting inflammatory responses, these compounds appear to have significant potential in the treatment of chronic inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…We have previously reported that several analogs of morphinans, such as naloxone, naltrexone or dextromethorphan are potent anti-inflammatory and neuroprotective compounds (Zhang et al 2004). Naloxone and naltrexone are non-selective antagonists of the G-protein-coupled opioid receptors.…”

Section: Therapies Using Morphinan-related Anti-inflammatory Compoundmentioning

confidence: 99%

Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy

2010

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Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Increasing evidence has demonstrated that inflammation is the fundamental process contributing to neuron death in PD. Neuroinflammation, which is characterized by activated microglia and infiltrating T cells at sites of neuronal injury, is a prominent contributor to the pathogenesis of progressive PD. Microglia play a critical role in forming a self-propelling cycle leading to sustained chronic neuroinflammation and driving the progressive neurodegeneration in PD. This activation depends heavily on the respiratory burst within the microglia, which in turn regulates a number of downstream pro-inflammatory activities. On the other hand, the adaptive immune responses, most notably T cells, are now emerging as important components of the inflammatory response that contribute to the pathogenesis of PD. This review paper focus on the understanding of the inflammatory etiology of PD, as well as the molecular signaling involved in this inflammatory response, with the aim to provide more effective treatments to slow down or halt the progression of chronic inflammation-induced CNS disorders, such as PD.

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“…These compounds include IL-10 [95, 96], TGF β 1 [97, 98], morphinan derivatives [99], and DPI, an inhibitor of oxidative stress responses [100]. It is well known that while these compounds have numerous regulatory effects on multiple biological targets, one of their primary anti-inflammatory features is the inhibition of NF- κ B within macrophages and microglial cells [101].…”

Section: Nf-κb and Da Neuroinflammationmentioning

confidence: 99%

Transcriptional Factor NF-κB as a Target for Therapy in Parkinson's Disease

Flood

Peterson

et al. 2011

Parkinson's Disease

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Parkinson's disease (PD) is a neurodegenerative condition characterized by chronic inflammation. Nuclear factor κB (NF-κB) is a family of inducible transcription factors that are expressed in a wide variety of cells and tissues, including microglia, astrocytes, and neurons, and the classical NF-κB pathway plays a key role in the activation and regulation of inflammatory mediator production during inflammation. Activation of the classical NF-κB pathway is mediated through the activity of the IKK kinase complex, which consists of a heterotrimer of IKKα, IKKβ, and IKKγ subunits. Targeting NF-κB has been proposed as an approach to the treatment of acute and chronic inflammatory conditions, and the use of inhibitors specific for either IKKβ or IKKγ has now been found to inhibit neurodegeneration of TH+ DA-producing neurons in murine and primate models of Parkinson's disease. These studies suggest that targeting the classical pathway of NF-κB through the inhibition of the IKK complex can serve as a useful therapeutic approach to the treatment of PD.

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Morphinan Neuroprotection: New Insight into the Therapy of Neurodegeneration

Cited by 10 publications

References 94 publications

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

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

Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy

Transcriptional Factor NF-κB as a Target for Therapy in Parkinson's Disease

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