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
