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.

Effects of cerium oxide nanoparticles on the growth of keratinocytes, fibroblasts and vascular endothelial cells in cutaneous wound healing

“…These methods were similar to those described previously [7]. All experiments were performed using 3–4 month-old male C57BL/6 mice.…”

“…The measurements were done without knowledge of the treatment history of the mice. Wound area was calculated using digital planimetry; linear healing progress was determined using the standard formula [7]. …”

“…The cells were then visualized by microscopy and tube formation was quantified as described previously [7]. Analysis of migration of keratinocytes, fibroblasts and HMEC-1 cells was performed using Transwell membrane filters (Corning, Costar) containing a polycarbonate filter with 8 mm pores.…”

“…Levels of endogenous antioxidants such as glutathione and vitamin E are diminished under conditions that impair wound healing including aging and diabetes [3]. The potential for exogenous antioxidants to enhance wound healing has been tested in only a few studies using animal models with variable results [4–7]. …”

Endoplasmic Reticulum Ca2+Handling in Excitable Cells in Health and Disease

“…It is noteworthy that recent findings suggest that individuals with relatively higher plasma uric acid levels are at reduced risk of developing Alzheimer disease (Irizarry et al, 2009), and uric acid protected cultured neurons from being killed by amyloid ␤-peptide (Guo et al, 1999). Uric acid analogs with increased solubility were reported to protect the brain against ischemic injury (Haberman et al, 2007) and to accelerate cutaneous wound healing (Chigurupati et al, 2010). However, the relative contributions of the inherent antioxidant activity of uric acid, versus its potential actions on ryanodine receptors, to the beneficial effects of uric acid in these experimental models remains to be determined.…”