Scott Gwen S, Cuzzocrea Salvatore, Genovese Tiziana, Koprowski Hilary, Hooper D Craig
Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3483-8. doi: 10.1073/pnas.0500307102. Epub 2005 Feb 22.
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.
过氧亚硝酸盐通过多种机制参与各种神经退行性疾病的发病过程，并且被认为介导脊髓损伤（SCI）后的继发性神经元细胞死亡。在此，我们证实生理相关水平的尿酸（UA），一种某些过氧亚硝酸盐介导反应的选择性抑制剂，在体外可阻断过氧亚硝酸盐对原代脊髓神经元的毒性作用。此外，在小鼠模型中于脊髓损伤发作时给予UA可抑制脊髓中的几种病理变化，包括一般组织损伤、硝基酪氨酸形成、脂质过氧化、聚（ADP - 核糖）聚合酶激活以及中性粒细胞浸润。更重要的是，UA治疗可改善损伤后的功能恢复。综上所述，我们的研究结果支持过氧亚硝酸盐参与脊髓损伤后继发性损伤病理生理学的概念。它们还提出升高UA水平可能为治疗脊髓损伤以及其他具有过氧亚硝酸盐介导病理成分的神经疾病提供一种治疗方法的可能性。
