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Exp Clin Endocrinol Diabetes 2013; 121(02): 84-89
DOI: 10.1055/s-0032-1333279
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Epalrestat Improves Diabetic Wound Healing via Increased Expression of Nerve Growth Factor

O. Nakagaki
1   Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Japan
,
H. Miyoshi
1   Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Japan
,
T. Sawada
1   Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Japan
,
T. Atsumi
1   Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Japan
,
T. Kondo
1   Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Japan
,
T. Atsumi
1   Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Japan
› Author Affiliations
Further Information

Publication History

received 29 November 2012
first decision 29 November 2012

accepted 02 January 2013

Publication Date:
20 February 2013 (online)

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Abstract

Aims/Introduction:

Aldose reductase inhibitors (ARIs) are a useful therapy for diabetic neuropathy. Nerve damage is associated with delayed wound healing of skin ulcers in diabetic patients. Therefore, we hypothesized that ARI supplementation would improve diabetic wound healing.

Materials and methods:

Control and streptozotocin-induced diabetic mice were fed either control diet or diet containing the ARI Epalrestat (40 mg/kg). After 12 weeks, we created skin wounds on the backs of the mice. Wound healing was determined by measuring the reduction in wound area.

Results:

The wound gap of the diabetic group was significantly larger 9 days after creating the wounds when compared to the other groups (p<0.01). Interestingly, wound healing in the diabetic mice fed Epalrestat was comparable to the non-diabetic mice. To clarify the mechanism(s) behind this improved wound healing, mRNA expression of growth factors reported to be involved in wound healing were examined. Among the growth factors investigated, only the expression of nerve growth factor (NGF) was ­significantly decreased (54.0%) in the healing lesions of diabetic mice. Similarly, NGF protein expression was decreased in diabetic mice and recovered in Epalrestat treated diabetic mice. Inhibition of NGF via 2 separate inhibitors (K252a and BSO) reduced the ability of Epalrestat to improve wound healing in diabetic mice.

Conclusions:

These findings suggest that Epalrestat is a potential therapy for improving diabetic wound healing and the mechanism involves upregulation of NGF.

Key words

aldose reductase inhibitor - wound healing - nerve growth factor
 

  • References

  • 1 Chalk C, Benstead TJ, Moore F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. 2007
    PubMedGoogle Scholar
  • 2 Chudzik W, Kaczorowska B, Przybyla M et al. Diabetic neuropathy. Pol Merkur Lekarski 2007; 22: 66-69
    PubMedGoogle Scholar
  • 3 Baba LM, Kimura K, Suda T, Yagihashi S. Three-year inhibition of aldose reductase on development of symptomatic neuropathy in diabetic patients. Journal of the Peripheral Nervous System 2006; 11: 3
    PubMedGoogle Scholar
  • 4 Hara F, Samuel S, Liu J et al. A homeobox gene related to Drosophila distal-less promotes ovarian tumorigenicity by inducing expression of vascular endothelial growth factor and fibroblast growth factor-2. Am J Pathol 2007; 170: 1594-1606
    CrossrefPubMedGoogle Scholar
  • 5 Gibran NS, Jang YC, Isik FF et al. Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus. J Surg Res 2002; 108: 122-128
    CrossrefPubMedGoogle Scholar
  • 6 Barrientos S, Stojadinovic O, Golinko MS et al. Growth factors and cytokines in wound healing. Wound Repair Regen 2008; 16: 585-601
    CrossrefPubMedGoogle Scholar
  • 7 Gurtner GC, Werner S, Barrandon Y et al. Wound repair and regeneration. Nature 2008; 453: 314-321
    CrossrefPubMedGoogle Scholar
  • 8 Muangman P, Muffley LA, Anthony JP et al. Nerve growth factor accelerates wound healing in diabetic mice. Wound Repair Regen 2004; 12: 44-52
    CrossrefPubMedGoogle Scholar
  • 9 Fujimoto J, Limuro Y. Growth factor. Surgery Frontier 2007; 14: 1
    PubMedGoogle Scholar
  • 10 Barker AR, Rosson GD, Dellon AL. Wound Healing in Denervated Tissue. Ann Plast Surg 2006; 57: 4
    PubMedGoogle Scholar
  • 11 Pradhan L, Nabzdyk C, Andersen ND et al. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med 2009; 11
    PubMedGoogle Scholar
  • 12 Nishihara R, Sugano N, Takano M et al. The effect of Porphyromonas gingivalis infection on cytokine levels in type 2 diabetic mice. J Periodontal Res 2009; 44: 305-310
    CrossrefPubMedGoogle Scholar
  • 13 Strissel KJ, Stancheva Z, Miyoshi H et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 2007; 56: 2910-2918
    CrossrefPubMedGoogle Scholar
  • 14 Stefanato CM, Yaar M, Bhawan J et al. Modulations of nerve growth factor and Bcl-2 in ultraviolet-irradiated human epidermis. J Cutan Pathol 2003; 30: 351-357
    CrossrefPubMedGoogle Scholar
  • 15 Zhou Z, Kawana S, Aoki E et al. Dynamic changes in nerve growth factor and substance P in the murine hair cycle induced by depilation. J Dermatol 2006; 33: 833-841
    CrossrefPubMedGoogle Scholar
  • 16 Graiani G, Emanueli C, Desortes E et al. Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice. Diabetologia 2004; 47: 1047-1054
    PubMedGoogle Scholar
  • 17 Liu Y, Cai S, Shu XZ et al. Release of basic fibroblast growth factor from a crosslinked glycosaminoglycan hydrogel promotes wound healing. Wound Repair Regen 2007; 15: 245-251
    CrossrefPubMedGoogle Scholar
  • 18 Yoshida S, Matsumoto K, Tomioka D et al. Recombinant hepatocyte growth factor accelerates cutaneous wound healing in a diabetic mouse model. Growth Factors 2004; 22: 111-119
    CrossrefPubMedGoogle Scholar
  • 19 Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24: 1217-1281
    CrossrefPubMedGoogle Scholar
  • 20 Ohi T, Saita K, Furukawa S et al. Therapeutic effects of aldose reductase inhibitor on experimental diabetic neuropathy through synthesis/secretion of nerve growth factor. Exp Neurol 1998; 151: 215-220
    CrossrefPubMedGoogle Scholar
  • 21 Tomlinson DR, Fernyhough P, Diemel LT. Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors. Diabetes 1997; 46: 43-49
    CrossrefPubMedGoogle Scholar
  • 22 Matsuda H, Koyama H, Sato H et al. Role of nerve growth factor in cutaneous wound healing: accelerating effects in normal and healing-impaired diabetic mice. J Exp Med 1998; 187: 297-306
    CrossrefPubMedGoogle Scholar
  • 23 Apfel SC, Kessler JA, Adornato BT et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology 1998; 51: 695-702
    PubMedGoogle Scholar
  • 24 McArthur JC, Yiannoutsos C, Simpson DM et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 2000; 54: 1080-1088
    CrossrefPubMedGoogle Scholar
  • 25 Apfel SC, Schwartz S, Adornato BT et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group. JAMA: the journal of the American Medical Association 2000; 284: 2215-2221
    CrossrefPubMedGoogle Scholar
  • 26 Generini S, Tuveri MA, Matucci Cerinic M et al. Topical application of nerve growth factor in human diabetic foot ulcers. A study of three cases. Experimental and clinical endocrinology & diabetes: official journal. German Society of Endocrinology [and] German Diabetes Association 2004; 112: 542-544
    PubMedGoogle Scholar
  • 27 Tiaka EK, Papanas N, Manolakis AC et al. The role of hyperbaric oxygen in the treatment of diabetic foot ulcers. Angiology 2012; 63: 302-314 DOI: 10.1177/0003319711416804.
    CrossrefPubMedGoogle Scholar
  • 28 Riaz S, Malcangio M, Miller M et al. A vitamin D(3) derivative (CB1093) induces nerve growth factor and prevents neurotrophic deficits in streptozotocin-diabetic rats. Diabetologia 1999; 42: 1308-1313
    CrossrefPubMedGoogle Scholar
  • 29 Calcutt NA, Freshwater JD, Hauptmann N et al. Protection of sensory function in diabetic rats by Neotrofin. European journal of pharmacology 2006; 534: 187-193
    CrossrefPubMedGoogle Scholar
  • 30 Suzuki T, Sekido H, Kato N et al. Neurotrophin-3-induced production of nerve growth factor is suppressed in Schwann cells exposed to high glucose: involvement of the polyol pathway. J Neurochem 2004; 91: 1430-1438
    CrossrefPubMedGoogle Scholar