title: 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.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
authors.forename: Gwen S
authors.initials: GS
authors.lastname: Scott
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Hilary
authors.initials: H
authors.lastname: Koprowski
authors.forename: D Craig
authors.initials: DC
authors.lastname: Hooper
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D014527:Uric Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D030421:Peroxynitrous Acid; D014527:Uric Acid; D009195:Peroxidase
references.citation: Arch Biochem Biophys. 1999 Dec 15;372(2):285-94
references.pmid: 10600166
references.citation: Pharmacol Toxicol. 2003 Dec;93(6):284-9
references.pmid: 14675462
references.citation: Arch Biochem Biophys. 2000 Apr 15;376(2):333-7
references.pmid: 10775420
references.citation: Eur J Pharmacol. 2000 Jul 14;400(1):19-33
references.pmid: 10913581
references.citation: Neurosci Lett. 2000 Oct 6;292(2):137-41
references.pmid: 10998568
references.citation: J Neurochem. 2000 Nov;75(5):2144-54
references.pmid: 11032904
references.citation: J Immunol. 2000 Dec 1;165(11):6511-8
references.pmid: 11086092
references.citation: Ann Neurol. 2001 Jan;49(1):139
references.pmid: 11198290
references.citation: Free Radic Res. 2000 Dec;33(6):771-84
references.pmid: 11237099
references.citation: J Neurol. 2001 Feb;248(2):121-6
references.pmid: 11284129
references.citation: J Neurotrauma. 2001 Apr;18(4):369-76
references.pmid: 11336438
references.citation: J Neurotrauma. 2001 May;18(5):523-32
references.pmid: 11393255
references.citation: Acta Neurochir Suppl. 2000;76:61-4
references.pmid: 11450092
references.citation: Mult Scler. 2001 Jun;7(3):165-6
references.pmid: 11475439
references.citation: Eur J Pharmacol. 2001 Aug 10;425(2):149-52
references.pmid: 11502281
references.citation: Bioessays. 2001 Sep;23(9):795-806
references.pmid: 11536292
references.citation: J Immunol. 2001 Sep 15;167(6):3470-7
references.pmid: 11544340
references.citation: J Neurotrauma. 2002 Feb;19(2):175-90
references.pmid: 11893021
references.citation: Eur J Neurol. 2002 May;9(3):221-6
references.pmid: 11985629
references.citation: Ann N Y Acad Sci. 2002 May;962:242-59
references.pmid: 12076979
references.citation: Free Radic Biol Med. 2002 Nov 15;33(10):1363-71
references.pmid: 12419468
references.citation: Neuroscience. 2002;115(3):839-49
references.pmid: 12435422
references.citation: Eur J Pharmacol. 2004 Jan 1;483(1):79-93
references.pmid: 14709329
references.citation: J Neurochem. 2004 Mar;88(6):1335-44
references.pmid: 15009633
references.citation: Neuroreport. 2004 May 19;15(7):1163-6
references.pmid: 15129166
references.citation: J Neuroimmunol. 2004 Oct;155(1-2):32-42
references.pmid: 15342194
references.citation: J Neurotrauma. 2004 Sep;21(9):1255-63
references.pmid: 15453994
references.citation: Anal Biochem. 1979 Jun;95(2):351-8
references.pmid: 36810
references.citation: J Pharmacol Methods. 1985 Nov;14(3):157-67
references.pmid: 2997548
references.citation: Gene. 1991 Dec 30;109(2):281-4
references.pmid: 1765273
references.citation: J Mol Evol. 1992 Jan;34(1):78-84
references.pmid: 1556746
references.citation: J Neurotrauma. 1992 Mar;9 Suppl 1:S1-7
references.pmid: 1588600
references.citation: Neurol Res. 1992 Mar;14(1):49-52
references.pmid: 1351259
references.citation: J Am Geriatr Soc. 1993 May;41(5):501-6
references.pmid: 8486882
references.citation: Ann Emerg Med. 1993 Jun;22(6):987-92
references.pmid: 8503537
references.citation: J Neural Transm Park Dis Dement Sect. 1993;6(2):119-26
references.pmid: 8117408
references.citation: Brain Res Bull. 1994;33(4):419-25
references.pmid: 8124580
references.citation: J Neurochem. 1995 May;64(5):1965-72
references.pmid: 7722484
references.citation: Am J Epidemiol. 1996 Sep 1;144(5):480-4
references.pmid: 8781463
references.citation: Exp Neurol. 1996 Dec;142(2):258-75
references.pmid: 8934558
references.citation: J Comp Neurol. 1997 Jan 20;377(3):443-64
references.pmid: 8989657
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2528-33
references.pmid: 9122229
references.citation: Neuroscience. 1997 Aug;79(4):1177-82
references.pmid: 9219976
references.citation: J Neurochem. 1998 Feb;70(2):501-8
references.pmid: 9453543
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):675-80
references.pmid: 9435251
references.citation: Exp Neurol. 1998 May;151(1):77-88
references.pmid: 9582256
references.citation: J Neurosci Res. 1998 Sep 1;53(5):613-25
references.pmid: 9726432
references.citation: Ann Neurol. 1999 Jan;45(1):120-4
references.pmid: 9894885
references.citation: Neurosurgery. 1999 May;44(5):1027-39; discussion 1039-40
references.pmid: 10232536
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16303-8
references.pmid: 12451183
references.citation: Glia. 2003 Jan 15;41(2):105-16
references.pmid: 12509801
references.citation: Toxicol Lett. 2003 Apr 11;140-141:105-12
references.pmid: 12676456
references.citation: Ann N Y Acad Sci. 2003 May;993:217-28; discussion 287-8
references.pmid: 12853316
references.citation: Neurobiol Aging. 2003 Nov;24(7):915-9
references.pmid: 12928050
references.citation: J Neurosci Res. 2003 Oct 15;74(2):227-39
references.pmid: 14515352
references.citation: J Neuropathol Exp Neurol. 2003 Nov;62(11):1096-107
references.pmid: 14656068
references.citation: Neurosci Lett. 1999 Apr 30;266(1):61-4
references.pmid: 10336184
references.citation: J Neurochem. 1999 Aug;73(2):684-92
references.pmid: 10428065
references.citation: FASEB J. 2000 Apr;14(5):691-8
references.pmid: 10744626