Neuroprotective effects of urate are mediated by augmenting astrocytic glutathione synthesis and release.
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.
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, United States. Electronic address: rbakshi1@mgh.harvard.edu.
Rachit
R
Bakshi
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, United States; Department of Neurobiology, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Hong
H
Zhang
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, United States.
Robert
R
Logan
Department of Dermatology, Massachusetts General Hospital, Boston, MA 02129, United States.
Ila
I
Joshi
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, United States.
Yuehang
Y
Xu
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, United States.
Xiqun
X
Chen
Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, United States.
Michael A
MA
Schwarzschild
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014527:Uric Acid / Q000494:pharmacology*
D017077:Culture Media, Conditioned; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D014527:Uric Acid; D005978:Glutathione
Astrocytes; Glutathione; Neurons; Nrf2; Urate