The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

Hooper, D. Craig; Kean, Rhonda; Scott, G.; Spitsin, Sergei; Mikheeva, Tatiana; Morimoto, Kanehisa; Bette, Michael; Röhrenbeck, Annette M.; Dietzschold, Bernhard; Weihe, Eberhard

doi:10.4049/jimmunol.167.6.3470

Cited by 73 publications

(53 citation statements)

References 45 publications

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“…In addition, it has been demonstrated that inhibition of iNOS reduces the disruption of the blood-spinal cord barrier, neutrophil accumulation, and neuronal cell death after contusion SCI (36). This suggested to us that peroxynitrite may trigger the induction of blood-spinal cord barrier permeability changes in SCI, as is evidently the case in other models (24,26,34,35). The foremost protective effect of UA in SCI would therefore be manifested in the suppression of the acute inflammatory response.…”

Section: Discussionmentioning

confidence: 88%

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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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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Section: Discussionmentioning

confidence: 88%

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

114

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“…Using UA administration to probe the effects of peroxynitrite in CNS inflammation, we have discovered that it contributes not only to CNS tissue damage but also to enhanced BBB permeability and immune cell invasion into the CNS (11)(12)(13)22). Peripheral aspects of the immune response that leads to CNS inflammation, such as the up-regulation of iNOS expression by monocytes, are unchanged by UA treatment (12,13).…”

Section: Discussionmentioning

confidence: 96%

“…Moreover, UA treatment of mice with EAE promotes their recovery (10,11). The therapeutic effects of UA in EAE and other animal models of CNS inflammation (10)(11)(12)(13)22), together with evidence of an inverse correlation between serum UA levels and the incidence of MS, have renewed interest in the specificity of this purine metabolite. Although UA has long been recognized as an antioxidant (2), recent observations suggest that it is not a general antioxidant but a specific inhibitor of radicals generated by the decomposition of peroxynitrite, the product of NO and superoxide, in a biological milieu (4, 5).…”

Section: Discussionmentioning

confidence: 99%

“…Nitrite accumulation in the medium was assessed by using the Griess reaction as detailed (10). The activation of iNOS genes was assessed by real-time quantitative RT-PCR analysis of the expression of the specific mRNAs by using a Bio-Rad (Hercules, CA) iCycler iQ real-time detection system as detailed (22). Data were calculated based on a threshold cycle (Ct), determined as the cycle with a signal higher than that of the background (signal detected in cycles 2-10) plus 10 times its SD.…”

Section: Activation Of Monocytes and Assessment Of Inos Activity In Vmentioning

confidence: 99%

“…UA is an intermediate of purine metabolism in most mammals but, because of the unusual penetrance of a single point mutation in the urate oxidase gene, is the end product in higher-order primates and humans (19)(20)(21). When the normally low serum levels of UA in animals used to model neuroinflammatory disease are raised by repeated administration of UA, they become resistant to the induction of such diseases, which include experimental allergic encephalomyelitis (EAE) and Borna disease (8,(10)(11)(12)(13)22). Moreover, studies in EAE have demonstrated that treatment of an ongoing neuroinflammatory condition with UA has beneficial effects (10,11).…”

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confidence: 99%

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Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors

Scott

Spitsin

Kean

et al. 2002

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

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117

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Uric acid (UA) is a purine metabolite that selectively inhibits peroxynitrite-mediated reactions implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative diseases. Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low serum UA levels and individuals with hyperuricemia (gout) rarely develop the disease. Moreover, the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE), an animal model of MS. Thus, raising serum UA levels in MS patients, by oral administration of a UA precursor such as inosine, may have therapeutic value. We have assessed the effects of inosine, as well as inosinic acid, on parameters relevant to the chemical reactivity of peroxynitrite and the pathogenesis of EAE. Both had no effect on chemical reactions associated with peroxynitrite, such as tyrosine nitration, or on the activation of inflammatory cells in vitro. Moreover, when mice treated with the urate oxidase inhibitor potassium oxonate were fed inosine or inosinic acid, serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in serum inosine was detected. Administration of inosinic acid suppressed the appearance of clinical signs of EAE and promoted recovery from ongoing disease. The therapeutic effect on animals with active EAE was associated with increased UA, but not inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of inosine and inosinic acid in EAE is via their metabolism to UA.

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Role of Nitric Oxide in the Onset of Facial Nerve Palsy by HSV-1 Infection

Hato

Kohno

Yamada

et al. 2013

JAMA Otolaryngol Head Neck Surg

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These findings suggest that NO produced by inducible NO synthase in the facial nerve plays an important role in the onset of facial palsy caused by HSV-1 infection, which is considered a causative virus of Bell palsy. Hato and colleagues elucidate the role of nitric oxide in HSV-1–related facial nerve paralysis in mice and evaluate the role of edaravone, a free radical scavenger, in preventing the paralysis.

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The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

Cited by 73 publications

References 45 publications

Uric acid protects against secondary damage after spinal cord injury

Uric acid protects against secondary damage after spinal cord injury

Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors

Role of Nitric Oxide in the Onset of Facial Nerve Palsy by HSV-1 Infection

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