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Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release

Authors :
Rachit Bakshi
Hong Zhang
Robert Logan
Ila Joshi
Yuehang Xu
Xiqun Chen
Michael A. Schwarzschild
Source :
Neurobiology of Disease, Vol 82, Iss , Pp 574-579 (2015)
Publication Year :
2015
Publisher :
Elsevier, 2015.

Abstract

Urate has emerged as a promising target for neuroprotection based on epidemiological observations, preclinical models, and early clinical trial results in multiple neurologic diseases, including Parkinson's disease (PD). This study investigates the astrocytic mechanism of urate's neuroprotective effect. Targeted biochemical screens of conditioned medium from urate- versus vehicle-treated astrocytes identified markedly elevated glutathione (GSH) concentrations as a candidate mediator of urate's astrocyte-dependent neuroprotective effects. Urate treatment also induced the nuclear translocation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein and transcriptional activation of its key target genes in primary astrocytic cultures. Urate's neuroprotective effect was attenuated when GSH was depleted in the conditioned media either by targeting its synthesis or release by astrocytes. Overall, these results implicate GSH as the extracellular astrocytic factor mediating the protective effect of urate in a cellular model of PD. These results also show that urate can employ a novel indirect neuroprotective mechanism via induction of the Nrf2 signaling pathway, a master regulator of the response to oxidative stress, in astrocytes.

Details

Language :
English
ISSN :
1095953X
Volume :
82
Issue :
574-579
Database :
Directory of Open Access Journals
Journal :
Neurobiology of Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.13d37869ae54217825107be6986be31
Document Type :
article
Full Text :
https://doi.org/10.1016/j.nbd.2015.08.022