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Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity.
J Neuroinflammation. 2008 May 28; 5:21.JN

Abstract

BACKGROUND

Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD) through over-activation of microglia, which consequently causes the excessive production of proinflammatory and neurotoxic factors, and impacts surrounding neurons and eventually induces neurodegeneration. Hence, prevention of microglial over-activation has been shown to be a prime target for the development of therapeutic agents for inflammation-mediated neurodegenerative diseases.

METHODS

For in vitro studies, mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanism by which FLZ, a squamosamide derivative, mediates anti-inflammatory and neuroprotective effects in both lipopolysaccharide-(LPS)- and 1-methyl-4-phenylpyridinium-(MPP+)-mediated models of PD. For in vivo studies, a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-(MPTP-) induced PD mouse model was used.

RESULTS

FLZ showed potent efficacy in protecting dopaminergic (DA) neurons against LPS-induced neurotoxicity, as shown in rat and mouse primary mesencephalic neuronal-glial cultures by DA uptake and tyrosine hydroxylase (TH) immunohistochemical results. The neuroprotective effect of FLZ was attributed to a reduction in LPS-induced microglial production of proinflammatory factors such as superoxide, tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and prostaglandin E2 (PGE2). Mechanistic studies revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of NADPH oxidase (PHOX), the key microglial superoxide-producing enzyme. A critical role for PHOX in FLZ-elicited neuroprotection was further supported by the findings that 1) FLZ's protective effect was reduced in cultures from PHOX-/- mice, and 2) FLZ inhibited LPS-induced translocation of the cytosolic subunit of p47PHOX to the membrane and thus inhibited the activation of PHOX. The neuroprotective effect of FLZ demonstrated in primary neuronal-glial cultures was further substantiated by an in vivo study, which showed that FLZ significantly protected against MPTP-induced DA neuronal loss, microglial activation and behavioral changes.

CONCLUSION

Taken together, our results clearly demonstrate that FLZ is effective in protecting against LPS- and MPTP-induced neurotoxicity, and the mechanism of this protection appears to be due, at least in part, to inhibition of PHOX activity and to prevention of microglial activation.

Authors+Show Affiliations

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. zhangd2@niehs.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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., Intramural

Language

eng

PubMed ID

18507839

Citation

Zhang, Dan, et al. "Squamosamide Derivative FLZ Protects Dopaminergic Neurons Against Inflammation-mediated Neurodegeneration Through the Inhibition of NADPH Oxidase Activity." Journal of Neuroinflammation, vol. 5, 2008, p. 21.
Zhang D, Hu X, Wei SJ, et al. Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity. J Neuroinflammation. 2008;5:21.
Zhang, D., Hu, X., Wei, S. J., Liu, J., Gao, H., Qian, L., Wilson, B., Liu, G., & Hong, J. S. (2008). Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity. Journal of Neuroinflammation, 5, 21. https://doi.org/10.1186/1742-2094-5-21
Zhang D, et al. Squamosamide Derivative FLZ Protects Dopaminergic Neurons Against Inflammation-mediated Neurodegeneration Through the Inhibition of NADPH Oxidase Activity. J Neuroinflammation. 2008 May 28;5:21. PubMed PMID: 18507839.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity. AU - Zhang,Dan, AU - Hu,Xiaoming, AU - Wei,Sung-Jen, AU - Liu,Jie, AU - Gao,Huiming, AU - Qian,Li, AU - Wilson,Belinda, AU - Liu,Gengtao, AU - Hong,Jau-Shyong, Y1 - 2008/05/28/ PY - 2008/03/26/received PY - 2008/05/28/accepted PY - 2008/5/30/pubmed PY - 2008/9/23/medline PY - 2008/5/30/entrez SP - 21 EP - 21 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 5 N2 - BACKGROUND: Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD) through over-activation of microglia, which consequently causes the excessive production of proinflammatory and neurotoxic factors, and impacts surrounding neurons and eventually induces neurodegeneration. Hence, prevention of microglial over-activation has been shown to be a prime target for the development of therapeutic agents for inflammation-mediated neurodegenerative diseases. METHODS: For in vitro studies, mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanism by which FLZ, a squamosamide derivative, mediates anti-inflammatory and neuroprotective effects in both lipopolysaccharide-(LPS)- and 1-methyl-4-phenylpyridinium-(MPP+)-mediated models of PD. For in vivo studies, a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-(MPTP-) induced PD mouse model was used. RESULTS: FLZ showed potent efficacy in protecting dopaminergic (DA) neurons against LPS-induced neurotoxicity, as shown in rat and mouse primary mesencephalic neuronal-glial cultures by DA uptake and tyrosine hydroxylase (TH) immunohistochemical results. The neuroprotective effect of FLZ was attributed to a reduction in LPS-induced microglial production of proinflammatory factors such as superoxide, tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and prostaglandin E2 (PGE2). Mechanistic studies revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of NADPH oxidase (PHOX), the key microglial superoxide-producing enzyme. A critical role for PHOX in FLZ-elicited neuroprotection was further supported by the findings that 1) FLZ's protective effect was reduced in cultures from PHOX-/- mice, and 2) FLZ inhibited LPS-induced translocation of the cytosolic subunit of p47PHOX to the membrane and thus inhibited the activation of PHOX. The neuroprotective effect of FLZ demonstrated in primary neuronal-glial cultures was further substantiated by an in vivo study, which showed that FLZ significantly protected against MPTP-induced DA neuronal loss, microglial activation and behavioral changes. CONCLUSION: Taken together, our results clearly demonstrate that FLZ is effective in protecting against LPS- and MPTP-induced neurotoxicity, and the mechanism of this protection appears to be due, at least in part, to inhibition of PHOX activity and to prevention of microglial activation. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/18507839/Squamosamide_derivative_FLZ_protects_dopaminergic_neurons_against_inflammation_mediated_neurodegeneration_through_the_inhibition_of_NADPH_oxidase_activity_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-5-21 DB - PRIME DP - Unbound Medicine ER -