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Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase.
J Neuroinflammation. 2007 Sep 19; 4:23.JN

Abstract

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.

Authors+Show Affiliations

Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, North Carolina 27599, USA. qianl2@niehs.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17880684

Citation

Qian, Li, et al. "Sinomenine, a Natural Dextrorotatory Morphinan Analog, Is Anti-inflammatory and Neuroprotective Through Inhibition of Microglial NADPH Oxidase." Journal of Neuroinflammation, vol. 4, 2007, p. 23.
Qian L, Xu Z, Zhang W, et al. Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. J Neuroinflammation. 2007;4:23.
Qian, L., Xu, Z., Zhang, W., Wilson, B., Hong, J. S., & Flood, P. M. (2007). Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. Journal of Neuroinflammation, 4, 23.
Qian L, et al. Sinomenine, a Natural Dextrorotatory Morphinan Analog, Is Anti-inflammatory and Neuroprotective Through Inhibition of Microglial NADPH Oxidase. J Neuroinflammation. 2007 Sep 19;4:23. PubMed PMID: 17880684.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase. AU - Qian,Li, AU - Xu,Zongli, AU - Zhang,Wei, AU - Wilson,Belinda, AU - Hong,Jau-Shyong, AU - Flood,Patrick M, Y1 - 2007/09/19/ PY - 2007/05/16/received PY - 2007/09/19/accepted PY - 2007/9/21/pubmed PY - 2007/12/13/medline PY - 2007/9/21/entrez SP - 23 EP - 23 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 4 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/17880684/Sinomenine_a_natural_dextrorotatory_morphinan_analog_is_anti_inflammatory_and_neuroprotective_through_inhibition_of_microglial_NADPH_oxidase_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-4-23 DB - PRIME DP - Unbound Medicine ER -