Reaction of Uric Acid with Peroxynitrite and Implications for the Mechanism of Neuroprotection by Uric Acid

Squadrito, G; Cueto, Rafael; Splenser, Andres E.; Valavanidis, Athanasios; Zhang, Houwen; Uppu, Rao M.; Pryor, William A.

doi:10.1006/abbi.2000.1721

Cited by 314 publications

(212 citation statements)

References 28 publications

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“…Uric Acid an endogenous aqueous antioxidant in humans contributes as much as 2/3 rd of all free radical scavenging capacity in plasma (9). it is particularly effective in quenching hydroxyl,superoxide, peroxal and peroxynitrite radical and may serve protective physiological role by preventing lipid per oxidation.…”

Section: Resultsmentioning

confidence: 99%

Uric acid a better scavenger of free radicals than vitamin C in rheumatoid arthritis

Mahajan¹,

Kaur

Rawal

et al. 2009

Indian J Clin Biochem

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Section: Resultsmentioning

confidence: 99%

Uric acid a better scavenger of free radicals than vitamin C in rheumatoid arthritis

Mahajan¹,

Kaur

Rawal

et al. 2009

Indian J Clin Biochem

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“…The association of low-normal serum urate levels with Parkinson's disease and multiple sclerosis has led to proposals that higher PUA protects neurons from toxic effects of peroxynitrite (7,(41)(42)(43). However, urate concentration in brain is much lower than in plasma (7,44,45); urate is a poor scavenger of peroxynitrite (46)(47)(48); and reactions of urate with free radicals have pro-as well as antioxidant consequences (46,47,49,50). Moreover, significantly raising serum urate concentration for 2 years was of no benefit in patients with relapsing-remitting multiple sclerosis (51).…”

Section: Discussionmentioning

confidence: 99%

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

Hershfield

Roberts²,

Ganson³

et al. 2010

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

124

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A high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support rests largely on in vitro data and epidemiologic associations. Pegloticase therapy generates H 2 O 2 while depleting urate, offering an in vivo test of the antioxidant hypothesis. We show that erythrocytes can efficiently eliminate H 2 O 2 derived from urate oxidation to prevent cell injury in vitro; during therapy, disulfide-linked peroxiredoxin 2 dimer did not accumulate in red blood cells, indicating that their peroxidase capacity was not exceeded. To assess oxidative stress, we monitored F2-Isoprostanes (F2-IsoPs) and protein carbonyls (PC), products of arachidonic acid and protein oxidation, in plasma of 26 refractory gout patients receiving up to five infusions of pegloticase at 3-wk intervals. At baseline, PUA was markedly elevated in all patients, and plasma F2-IsoP concentration was elevated in most. Pegloticase infusion rapidly lowered mean PUA to ≤1 mg/dL in all patients, and PUA remained low in 16 of 21 patients who completed treatment. F2-IsoP levels did not correlate with PUA and did not increase during 15 wk of sustained urate depletion. There also was no significant change in the levels of plasma PC. Because refractory gout is associated with high oxidative stress in spite of high PUA, and profoundly depleting uric acid did not increase lipid or protein oxidation, we conclude that urate is not a major factor controlling oxidative stress in vivo.

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“…UA effectively blocks peroxynitrite-mediated tyrosine nitration in vitro by a reaction with second-order kinetics (21). On the other hand, UA enhances the oxidation of low-density lipoproteins by peroxynitrite in vitro (39) and has variable effects on lipid peroxidation by other radicals (45).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that uric acid (UA), a selective inhibitor of certain peroxynitrite-mediated chemical reactions (21), is therapeutic in experimental allergic encephalomyelitis (EAE) (e.g., refs. [22][23][24], a neurodegenerative disease model.…”

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.

116

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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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Reaction of Uric Acid with Peroxynitrite and Implications for the Mechanism of Neuroprotection by Uric Acid

Cited by 314 publications

References 28 publications

Uric acid a better scavenger of free radicals than vitamin C in rheumatoid arthritis

Uric acid a better scavenger of free radicals than vitamin C in rheumatoid arthritis

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo

Uric acid protects against secondary damage after spinal cord injury

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