Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo

Yu, Zhiming; Bruce‐Keller, Annadora J.; Goodman, Yadong; Mattson, Mark P.

doi:10.1002/(sici)1097-4547(19980901)53:5<613::aid-jnr11>3.0.co;2-1

Cited by 316 publications

(215 citation statements)

References 66 publications

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“…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

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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...

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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

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“…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%

“…Neuroprotective [35] Neuroprotective in SCI, brain ischemia/stroke, MS [38][39][40][41] Clinical trials SURE-PD (phase II trial) [10] URICO-ICTUS (phase IIb/III trial in stroke) [42,43] PD = Parkinson's disease; ALS = amyotrophic lateral sclerosis; AD = Alzheimer's disease; HD = Huntington's disease; MSA = multiple system atrophy; MCI = mild cognitive impairment; SCI = spinal cord injury; MS = multiple sclerosis …”

Section: In Vivomentioning

confidence: 99%

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Paganoni

Schwarzschild

2017

Neurotherapeutics

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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.

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“…Not only has evidence of peroxynitrite production been detected in spinal cord tissues from rats after traumatic injury (5-7), but administration of a peroxynitrite donor directly into the rat spinal cord has been shown to cause neuronal cell death and neurological deficit (8). In addition, a number of previous reports have demonstrated that peroxynitrite is toxic for neurons, including primary spinal cord neurons, and neuronal cell lines in vitro (9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

“…[22][23][24], a neurodegenerative disease model. There is evidence that UA protects different neuronal cell populations from peroxynitrite-mediated toxicity (11,12). However, an additional aspect of the protective effect of UA in EAE is evidently directed at CNS inflammation, because UA treatment prevents the loss of blood-brain barrier (BBB) integrity that occurs in the disease, thereby inhibiting inflammatory cell infiltration (24)(25)(26)(27).…”

mentioning

confidence: 99%

Uric acid protects against secondary damage after spinal cord injury

Scott

Cuzzocrea

Genovese

et al. 2005

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

114

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Peroxynitrite contributes to the pathogenesis of various neurodegenerative disorders through multiple mechanisms and is thought to mediate secondary neuronal cell death after spinal cord injury (SCI). Here we establish that physiologically relevant levels of uric acid (UA), a selective inhibitor of certain peroxynitrite-mediated reactions, block the toxic effects of peroxynitrite on primary spinal cord neurons in vitro. Furthermore, administration of UA at the onset of SCI in a mouse model inhibits several pathological changes in the spinal cord including general tissue damage, nitrotyrosine formation, lipid peroxidation, activation of poly(ADP-ribose) polymerase, and neutrophil invasion. More importantly, UA treatment improves functional recovery from the injury. Taken together, our findings support the concept that peroxynitrite contributes to the pathophysiology of secondary damage after SCI. They also raise the possibility that elevating UA levels may provide a therapeutic approach for the treatment of SCI as well as other neurological diseases with a peroxynitrite-mediated pathological component.blood-brain barrier ͉ neutrophils ͉ peroxynitrite ͉ spinal cord neurons ͉ cytotoxicity A cascade of pathophysiological processes rapidly follows mechanical trauma to the spinal cord, resulting in secondary neuronal damage that can significantly exacerbate the original injury (1). An acute inflammatory response at the site of the initial lesion is at least partly responsible for this secondary spinal cord pathology (e.g., refs. 2-4). Among the inflammatory cells recruited to the injured area are macrophages͞microglia and neutrophils that can mediate tissue damage by producing a variety of cytotoxic factors including reactive nitrogen species (3-7). Several studies have implicated peroxynitrite, a molecule generated when nitric oxide and superoxide combine, in secondary neuronal damage after spinal cord injury (SCI) (5-7). Not only has evidence of peroxynitrite production been detected in spinal cord tissues from rats after traumatic injury (5-7), but administration of a peroxynitrite donor directly into the rat spinal cord has been shown to cause neuronal cell death and neurological deficit (8). In addition, a number of previous reports have demonstrated that peroxynitrite is toxic for neurons, including primary spinal cord neurons, and neuronal cell lines in vitro (9-13).Peroxynitrite is known to mediate several potentially destructive chemical reactions, including tyrosine nitration and lipid peroxidation (14). Mitochondrial respiration is directly inhibited by peroxynitrite and is an early marker of its cytotoxic effects (9,14). In addition, peroxynitrite causes DNA strand breakage, which activates the enzyme poly(ADP-ribose) polymerase (PARP), which in turn triggers a cascade of processes that often lead to cell death (14). Because increased nitrotyrosine formation, lipid peroxidation, and PARP activation have all been associated with secondary damage in spinal cord trauma (5-7, 14-20), it is possible that second...

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Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo

Cited by 316 publications

References 66 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

Uric acid protects against secondary damage after spinal cord injury

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