Astroglia‐mediated effects of uric acid to protect spinal cord neurons from glutamate toxicity

Du, Yangzhou; Chen, Christopher; Tseng, Chia-Yi; Eisenberg, Yuval; Firestein, Bonnie L.

doi:10.1002/glia.20472

Cited by 97 publications

(111 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By using complementary genetic approaches disrupting and overexpressing UOx, we have demonstrated that disruption of the UOx gene with a resultant rise in urate protects the nigrostriatal dopaminergic system, and conversely that transgenic overexpressson of UOx with a resultant fall in urate exacerbates dopaminergic neurodegeneration and resultant neurochemical and behavioral deficits in a 6-OHDA mouse model of PD. Neuroprotective effects of urate have been reported in various in vitro and in vivo experimental models of neurological disorders, including ischemic brain injury (13,14), multiple sclerosis (15), and spinal cord injury (16,17). However, evidence regarding urate in PD models is sparse and largely restricted to cellular models of the disease.…”

Section: Discussionmentioning

confidence: 99%

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

112

121

View full text Add to dashboard Cite

Urate is the end product of purine metabolism in humans, owing to the evolutionary disruption of the gene encoding urate oxidase (UOx). Elevated urate can cause gout and urolithiasis and is associated with cardiovascular and other diseases. However, urate also possesses antioxidant and neuroprotective properties. Recent convergence of epidemiological and clinical data has identified urate as a predictor of both reduced risk and favorable progression of Parkinson's disease (PD). In rodents, functional UOx catalyzes urate oxidation to allantoin. We found that UOx KO mice with a constitutive mutation of the gene have increased concentrations of brain urate. By contrast, UOx transgenic (Tg) mice overexpressing the enzyme have reduced brain urate concentrations. Effects of the complementary UOx manipulations were assessed in a mouse intrastriatal 6-hydroxydopamine (6-OHDA) model of hemiparkinsonism. UOx KO mice exhibit attenuated toxic effects of 6-OHDA on nigral dopaminergic cell counts, striatal dopamine content, and rotational behavior. Conversely, Tg overexpression of UOx exacerbates these morphological, neurochemical, and functional lesions of the dopaminergic nigrostriatal pathway. Together our data support a neuroprotective role of endogenous urate in dopaminergic neurons and strengthen the rationale for developing urate-elevating strategies as potential disease-modifying therapy for PD.U rate, the anionic component of uric acid, predominates at physiological pH. As an apparent consequence of mutations in the urate oxidase (UOx) gene during primate evolution, urate constitutes the enzymatic end product of purine metabolism in humans (1). There remains controversy over how the loss of UOx activity and the resultant high urate concentrations in hominoids may have been beneficial and whether it still is. On one hand, urate is considered a pathogenic factor in gout, urolithiasis, and nephropathy, and hyperuricemia is associated with other medical conditions, such as hypertension, cardiovascular disease, and metabolic syndrome (2). On the other hand, the loss of UOx activity through multiple independent mutations in hominoids presumably conferred evolutionary advantages. Urate possesses potent antioxidant properties. High urate levels may have provided an antioxidant defense against aging and cancer, thereby contributing to a prolonged hominoid life span (3). In addition, increased urate may mediate blood pressure homeostasis in low-salt environments. Furthermore, higher urate has been suggested to enhance human intelligence or motivational behaviors or promote neuronal integrity and function (4).Recently a series of population and clinical epidemiology studies have lent support to a potential neuroprotective effect of urate (5,6). These studies demonstrated a robust inverse link between urate levels and both the risk and clinical progression of Parkinson's disease (PD), one of the most common neurodegenerative diseases. Given the putative role of oxidative stress in the pathogenesis of PD (7), these studies have i...

show abstract

Section: Discussionmentioning

confidence: 99%

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

112

121

View full text Add to dashboard Cite

show abstract

“…Urate protected cultured spinal cord neurons from glutamate toxicity [37] and was neuroprotective in models of spinal cord injury, multiple sclerosis, brain injury, and stroke [38][39][40][41]56]. This growing literature suggests a potential neuroprotective role for urate beyond PD.…”

Section: Urate Is Neuroprotective In Several Preclinical Models Of Nementioning

confidence: 99%

“…At physiologically relevant concentrations, urate was also shown to enhance function and survival of dopaminergic neurons in primary cultures of rat ventral mesencephalon [53]. Interestingly, urate-mediated effects may require its accumulation in astrocytes, suggesting a noncell-autonomous mechanism for urate's neuroprotective activity [36,37]. The mechanisms underlying urate's neuroprotective effects are not completely clear, though recent in vitro studies have begun to shed light on urate's targets.…”

Section: Urate Is Neuroprotective In Several Preclinical Models Of Nementioning

confidence: 99%

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Paganoni

Schwarzschild

2017

Neurotherapeutics

View full text Add to dashboard Cite

Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.

show abstract

“…24 The microglia were detached from the flasks by mild shaking and applied to a nylon mesh to remove astrocytes and cell clumps. Cells were plated in 60-mm 2 dishes (8 ϫ 10 5 cells per dish) or 100-mm 2 dishes (2 ϫ 10 6 cells per dish).…”

Section: Glial Cell Culturementioning

confidence: 99%

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Chang

Song

Jeon

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Rotenone exposure has emerged as an environmental risk factor for inflammation-associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Herein, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death; instead, they exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. Notably, MPO, an HOClproducing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. MPO-exposed glial cells also display characteristics of activated cells, producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone-induced activated state of glia and promotes glial cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures with glial cells from Mpo ؊/؊ mice than in those from wildtype mice. Collectively, our data provide evidence that MPO has dual functionality under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain.

show abstract

Astroglia‐mediated effects of uric acid to protect spinal cord neurons from glutamate toxicity

Cited by 97 publications

References 40 publications

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Contact Info

Product

Resources

About