Comparison of uric acid and ascorbic acid in protection against EAE

Spitsin, Sergei; Scott, G.; Mikheeva, Tatiana; Zborek, Anna; Kean, Rhonda; Brimer, C.M.; Koprowski, Hilary; Hooper, D. Craig

doi:10.1016/s0891-5849(02)01048-1

Cited by 104 publications

(69 citation statements)

References 48 publications

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“…To probe the pathological contributions of peroxynitrite to secondary damage after SCI, we have used UA, a selective inhibitor of certain peroxynitrite-mediated chemistries including tyrosine nitration (37, 38) but not lipid peroxidation (38,39). UA has been extensively used as a neuroprotective agent and has been shown to inhibit CNS inflammation and BBB permeability changes in several models (24-27, 34, 35).…”

Section: Discussionmentioning

confidence: 99%

“…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). In an EAE model, where peroxynitrite makes a major contribution to pathology, UA treatment inhibits tyrosine nitration in lesions (24) but fails to significantly reduce lipid peroxidation (38). These observations raise the possibility that the chemistries responsible for lipid peroxidation as a consequence of SCI may not be susceptible to inactivation by UA.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Uric acid protects against secondary damage after spinal cord injury

Scott

Cuzzocrea

Genovese

et al. 2005

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

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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.

Self Cite

116

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“…Vitamin C treatment was not found to be protective in murine EAE and the authors explained this by the ambivalent role of vitamin C during oxidative stress (Spitsin et al, 2002). The latter should be taken into account when vitamin C supplementation to MS patients is considered.…”

Section: Cellular Antioxidant Defencementioning

confidence: 99%

“…Uric acid is a natural scavenger of peroxynitrite that inhibits clinical signs in EAE and MS patients (Hooper et al, 1998). Evaluation of more than 20 million patient records revealed MS and gout (hyperuricemic syndrome) to be mutually exclusive diseases, suggesting hyperuricaemia to protect against MS (Hooper et al, 1998;Spitsin et al, 2002). Furthermore, oral administration of the oxidant scavenger N-acetylcysteine (NAC) inhibited EAE (Lehmann et al, 1994).…”

Section: Oxidative Stress and Antioxidantsmentioning

confidence: 99%

Antioxidants and polyunsaturated fatty acids in multiple sclerosis

Meeteren¹,

Teunissen

Dijkstra

et al. 2005

Eur J Clin Nutr

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“…Similar to MS, EAE involves the accumulation of inflammatory cells expressing iNOS (NOS-2) in CNS tissue lesions (14,15). Evidence suggests that peroxynitrite, a downstream product of iNOS, can play an important role in the pathogenesis of MS and EAE (14,(16)(17)(18). However, mice lacking iNOS remain highly susceptible to the induction of EAE (19).…”

mentioning

confidence: 99%

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Fabis¹,

Scott²,

Kean³

et al. 2007

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

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Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the CNS that is used to model certain parameters of multiple sclerosis. To establish the relative contributions of T cell reactivity, the loss of blood-brain barrier (BBB) integrity, CNS inflammation, and lesion formation toward the pathogenesis of EAE, we assessed the incidence of EAE and these parameters in mice lacking NF-B, TNF-␣, IFN-␣␤ receptors, IFN-␥ receptors, and inducible nitric oxide synthase. Although increased myelin oligodendrocyte glycoprotein-specific T cell reactivity was generally associated with a more rapid onset or increased disease severity, the loss of BBB integrity and cell accumulation in spinal cord tissues was invariably associated with the development of neurological disease signs. Histological and real-time RT-PCR analyses revealed differences in the nature of immune/inflammatory cell accumulation in the spinal cord tissues of the different mouse strains. On the other hand, disease severity during the acute phase of EAE directly correlated with the extent of BBB permeability. Thus, the loss of BBB integrity seems to be a requisite event in the development of EAE and can occur in the absence of important inflammatory mediators.gene knockout mice ͉ multiple sclerosis

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Comparison of uric acid and ascorbic acid in protection against EAE

Cited by 104 publications

References 48 publications

Uric acid protects against secondary damage after spinal cord injury

Uric acid protects against secondary damage after spinal cord injury

Antioxidants and polyunsaturated fatty acids in multiple sclerosis

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

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