Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activityReportar como inadecuado

Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Neuroinflammation

, 5:21

First Online: 28 May 2008Received: 26 March 2008Accepted: 28 May 2008


BackgroundInflammation 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.

MethodsFor 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.

ResultsFLZ 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-α TNF-α, 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 p47 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.

ConclusionTaken 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.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-2094-5-21 contains supplementary material, which is available to authorized users.

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Autor: Dan Zhang - Xiaoming Hu - Sung-Jen Wei - Jie Liu - Huiming Gao - Li Qian - Belinda Wilson - Gengtao Liu - Jau-Shyong Hong

Fuente: https://link.springer.com/

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