title: A synthetic uric acid analog accelerates cutaneous wound healing in mice.
abstract: Wound healing is a complex process involving intrinsic dermal and epidermal cells, and infiltrating macrophages and leukocytes. Excessive oxidative stress and associated inflammatory processes can impair wound healing, and antioxidants have been reported to improve wound healing in animal models and human subjects. Uric acid (UA) is an efficient free radical scavenger, but has a very low solubility and poor tissue penetrability. We recently developed novel UA analogs with increased solubility and excellent free radical-scavenging properties and demonstrated their ability to protect neural cells against oxidative damage. Here we show that the uric acid analog (6, 8 dithio-UA, but not equimolar concentrations of UA or 1, 7 dimethyl-UA) modified the behaviors of cultured vascular endothelial cells, keratinocytes and fibroblasts in ways consistent with enhancement of the wound healing functions of all three cell types. We further show that 6, 8 dithio-UA significantly accelerates the wound healing process when applied topically (once daily) to full-thickness wounds in mice. Levels of Cu/Zn superoxide dismutase were increased in wound tissue from mice treated with 6, 8 dithio-UA compared to vehicle-treated mice, suggesting that the UA analog enhances endogenous cellular antioxidant defenses. These results support an adverse role for oxidative stress in wound healing and tissue repair, and provide a rationale for the development of UA analogs in the treatment of wounds and for modulation of angiogenesis in other pathological conditions.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, United States of America.
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Chigurupati
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Mughal
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Akanksha
authors.initials: A
authors.lastname: Baharani
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Ross
authors.initials: R
authors.lastname: Wheeler
authors.forename: Suresh
authors.initials: S
authors.lastname: Poosala
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D000975:Antioxidants; D002478:Cells, Cultured; D016166:Free Radical Scavengers; D051379:Mice; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D012867:Skin / Q000293:injuries* / Q000473:pathology; D012995:Solubility; D013438:Sulfhydryl Compounds; D013482:Superoxide Dismutase / Q000187:drug effects; D014527:Uric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D013438:Sulfhydryl Compounds; D014527:Uric Acid; D013482:Superoxide Dismutase
references.citation: Ann Plast Surg. 1997 Nov;39(5):516-23
references.pmid: 9374149
references.citation: Adv Nurse Pract. 2008 Jul;16(7):53-6
references.pmid: 19181159
references.citation: Nature. 2008 May 15;453(7193):314-21
references.pmid: 18480812
references.citation: J Cell Physiol. 1987 Oct;133(1):1-13
references.pmid: 2444604
references.citation: J Biol Chem. 2008 Sep 12;283(37):25492-25502
references.pmid: 18599481
references.citation: J Pathol. 2008 Aug;215(4):421-30
references.pmid: 18491289
references.citation: QJM. 2008 Sep;101(9):685-95
references.pmid: 18353793
references.citation: J Cell Biochem. 1991 Apr;45(4):346-52
references.pmid: 2045428
references.citation: Wound Repair Regen. 2008 Sep-Oct;16(5):585-601
references.pmid: 19128254
references.citation: Chin Med J (Engl). 2003 Jul;116(7):1029-33
references.pmid: 12890377
references.citation: Ann Plast Surg. 2006 Apr;56(4):394-8; discussion 399-400
references.pmid: 16557070
references.citation: Philos Trans R Soc Lond B Biol Sci. 2004 May 29;359(1445):839-50
references.pmid: 15293811
references.citation: Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1149-56
references.pmid: 19473187
references.citation: Circulation. 2004 Oct 19;110(16):2484-93
references.pmid: 15262829
references.citation: J Investig Dermatol Symp Proc. 2000 Dec;5(1):40-6
references.pmid: 11147674
references.citation: Pharmacol Res. 2008 Aug;58(2):165-71
references.pmid: 18617006
references.citation: Pharmacol Rep. 2005;57 Suppl:108-19
references.pmid: 16415491
references.citation: Clin Exp Dermatol. 2007 Nov;32(6):709-15
references.pmid: 17953639
references.citation: Biochem Biophys Res Commun. 2005 Jul 29;333(2):404-10
references.pmid: 15950945
references.citation: Diabetes Care. 1992 Nov;15(11):1598-604
references.pmid: 1468291
references.citation: World J Surg. 2007 Apr;31(4):654-63
references.pmid: 17372665
references.citation: Wound Repair Regen. 2002 Jan-Feb;10(1):52-8
references.pmid: 11983006
references.citation: J Invest Dermatol. 2007 May;127(5):998-1008
references.pmid: 17435785
references.citation: Free Radic Res. 1997 Feb;26(2):93-101
references.pmid: 9257121
references.citation: J Neurosci Res. 1998 Sep 1;53(5):613-25
references.pmid: 9726432
references.citation: Proc Natl Acad Sci U S A. 1981 Nov;78(11):6858-62
references.pmid: 6947260
references.citation: J Pharmacol Exp Ther. 2008 Jan;324(1):1-7
references.pmid: 17890445
references.citation: Biochim Biophys Acta. 2008 Nov;1780(11):1348-61
references.pmid: 18249195
references.citation: Ann N Y Acad Sci. 2004 Mar;1012:37-50
references.pmid: 15105254
references.citation: Crit Care Med. 2003 Aug;31(8 Suppl):S547-57
references.pmid: 12907885
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2528-33
references.pmid: 9122229
references.citation: Curr Opin Rheumatol. 1995 Jul;7(4):359-63
references.pmid: 7547116
references.citation: Int J Low Extrem Wounds. 2004 Sep;3(3):125-32
references.pmid: 15866803
references.citation: J Neurosci. 1998 Jan 15;18(2):687-97
references.pmid: 9425011
references.citation: Arch Gerontol Geriatr. 1984 Dec;3(4):321-48
references.pmid: 6532339
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3483-8
references.pmid: 15728348
references.citation: PLoS One. 2007 Nov 14;2(11):e1167
references.pmid: 18000539
references.citation: Neuromolecular Med. 2007;9(4):315-23
references.pmid: 17999205
references.citation: J Invest Dermatol. 1990 Dec;95(6):626-31
references.pmid: 2250104
references.citation: J Cell Biol. 2007 Nov 19;179(4):747-60
references.pmid: 18025307