Uric acid protects against secondary damage after spinal cord injury

Abstract

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...

Temporal and Spatial Dynamics of Peroxynitrite-Induced Oxidative Damage After Spinal Cord Contusion Injury

“…The current results, as well as those of earlier studies (Bao et al, 2003; Genovese et al, 2007; Liu et al, 2005; Scott et al, 1999; Scott et al, 2003; Scott et al, 2005; Xiong et al, 2007; Xiong and Hall, 2009), suggest that the administration of antioxidants that target PN or PN-derived radicals within the first hours after SCI should provide effective neuroprotection. In agreement with this idea, compounds that can either scavenge peroxynitrite such as uric acid (Scott et al, 2005) or FeTSPP (Genovese et al, 2007), or its derived free radicals such as tempol (Hillard et al, 2004; Xiong and Hall, 2009) have been reported to attenuate post-SCI spinal tissue damage.…”

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

“…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.…”

“…Urate is a potent antioxidant, and antioxidant properties of urate have been proposed to mediate its neuroprotective effects in most aforementioned studies (13)(14)(15)(16)(17)(18)(19)(20)(21). We investigated oxidative stress status in UOx KO and Tg mice and found higher protein carbonyls, one of the most commonly used markers of oxidative stress, in both.…”

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

“…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.…”

“…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 …”