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Comparison of Topical PDGF and Naltrexone on Full‐Thickness Diabetic Wound Healing
Author(s) -
Titunick Michelle Beth,
Cain Jarrett,
Zagon Ian,
McLaughlin Patricia
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.981.7
Subject(s) - medicine , naltrexone , wound healing , growth factor , platelet derived growth factor receptor , angiogenesis , diabetes mellitus , platelet derived growth factor , saline , diabetic foot , streptozotocin , amputation , opioid , pharmacology , surgery , receptor , endocrinology
Diabetes affects more than 29 million individuals in the US, and approximately 15% will develop chronic, non‐healing foot ulcers (DFU) that may result in amputation if left untreated. The current FDA‐approved DFU treatment is Regranex® which increases platelet derived growth factor (PDGF), but is expensive and has significant side‐effects. A new topical treatment utilizing naltrexone (NTX) to block classical opioid receptors as well as Opioid Growth Factor Receptor (OGFr) has been shown to accelerate full‐thickness cutaneous wounds in preclinical models of type1 and type 2 diabetes by increasing cell replication and angiogenesis. NTX blocks interaction of the inhibitory peptide OGF and OGFr; OGF is elevated in serum of diabetic humans and animals. To compare the efficacy of NTX and Regranex®, type 1 diabetes was induced in male Sprague Dawley rats (n=14) by injection of streptozotocin (40mg/kg i.p. on two consecutive days); control rats received vehicle only (n=13). Five weeks later, four 6 mm wounds were produced on the dorsum of each animal; wounds were randomly assigned treatment of PDGF (Regranex®), 0.03% NTX dissolved in moisturizing cream, or cream containing sterile saline (control). Residual wound size was photographically monitored over a 2 week period. DNA synthesis (BrdU integration), as well as PDGF and vascular epithelial growth factor (VEGF) expression were measured in wound tissue (3–4 rats per group) collected 1,2 and 4 days following surgery. Both NTX and Regranex® significantly accelerated wound closure in comparison to the vehicle‐treated wounds. By day 4 following surgery, there was a 1.2‐fold decrease in residual wound size in rats treated with either NTX or Regranex® relative to vehicle‐treated wounds, and by day 12, NTX‐treated wounds were reduced in size by 5‐fold relative to vehicle‐treated wounds. All wounds were <1% the original size by day 14. Four days post‐wounding, DNA synthesis was elevated 43% in diabetic rats receiving NTX relative to diabetic vehicle‐treated rats (p≤0.01). Immunohistochemical examination of wounds one day after surgery revealed that Regranex®‐treated diabetic rats had 139% more PDGF positive cells than vehicle‐treated diabetic rats (p≤0.01), whereas NTX‐treated diabetic rats exhibited approximately 78% increase in PDGF+ cells compared to vehicle‐treated rats (p≤0.05). At 2 days, NTX‐treatment resulted in a 55% increase in PDGF+ cells relative to controls, whereas the Regranex and controls were comparable. Four days after surgery there was a 44% increase in VEGF+ vessels in NTX‐treated diabetic rats (p≤0.001) relative to those receiving vehicle only and a 69% increase when compared to diabetic Regranex®‐treated rats (p≤0.001). FGF immunohistochemistry did not indicated significant differences in expression at wound sites between any treatment groups. The data suggest that blockade of the OGF‐OGFr regulatory pathway utilizing NTX may be a safe and effective alternative treatment to Regranex® for DFUs.