Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase.

Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Research Abstract Details 

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Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Abstract Text:

Li Qian,Zongli Xu,Wei Zhang,Belinda Wilson,Jau-Shyong Hong,Patrick M Flood,Li Qian,Zongli Xu,Wei Zhang,Belinda Wilson,Jau-Shyong Hong,Patrick M Flood,

BACKGROUND: The mechanisms involved in the induction and regulation of inflammation resulting in dopaminergic (DA) neurotoxicity in Parkinson's disease (PD) are complex and incompletely understood. Microglia-mediated inflammation has recently been implicated as a critical mechanism responsible for progressive neurodegeneration. METHODS: Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanisms of sinomenine (SN)-mediated anti-inflammatory and neuroprotective effects in both the lipopolysaccharide (LPS)- and the 1-methyl-4-phenylpyridinium (MPP+)-mediated models of PD. RESULTS: SN showed equivalent efficacy in protecting against DA neuron death in rat midbrain neuron-glial cultures at both micro- and sub-picomolar concentrations, but no protection was seen at nanomolar concentrations. The neuroprotective effect of SN was attributed to inhibition of microglial activation, since SN significantly decreased tumor necrosis factor-alpha (TNF-alpha, prostaglandin E2 (PGE2) and reactive oxygen species (ROS) production by microglia. In addition, from the therapeutic point of view, we focused on sub-picomolar concentration of SN for further mechanistic studies. We found that 10(-14) M of SN failed to protect DA neurons against MPP+-induced toxicity in the absence of microglia. More importantly, SN failed to show a protective effect in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells. Furthermore, we demonstrated that SN reduced LPS-induced extracellular ROS production through the inhibition of the PHOX cytosolic subunit p47phoxtranslocation to the cell membrane. CONCLUSION: Our findings strongly suggest that the protective effects of SN are most likely mediated through the inhibition of microglial PHOX activity. These findings suggest a novel therapy to treat inflammation-mediated neurodegenerative diseases.

Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Publishing Authors By Initials

L Qian,Z Xu,W Zhang,B Wilson,JS Hong,PM Flood,L Qian,Z Xu,W Zhang,B Wilson,JS Hong,PM Flood,

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Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: Journal of neuroinflammation

VOLUME: 4

Page Numbers: 23

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ISSN: 1742-2094

DAY: 19

MONTH: 09

YEAR: 2007

Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Information

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LANGUAGE: eng

NlmUniqueID: 101222974

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Grant and Affiliation Information for Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase.

AFFILIATION: Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, North Carolina 27599, USA. qianl2@niehs.nih.gov

Country: England

AGENCY: United States NIDCR

GRANT: DE-13079

ACRONYM: DE

MEDLINETA: J Neuroinflammation

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