Drug development can be costly and time consuming, and repurposing already approved therapeutics is a growing industry. A new report in PLoS One (Wang et al. 2015) demonstrates that sildenafil (aka Viagra®, Revatio®), a well-known drug that increases blood flow and is used to treat erectile dysfunction and pulmonary hypertension, improves neurovascular functions and ameliorates long-term peripheral neuropathy in middle-aged diabetic mice. This report echoes the findings of a case report study from 2006 indicating that diabetic patients treated for erectile dysfunction with a phosphodiesterase type 5 inhibitor reported improvement in their symptoms relating to peripheral neuropathy and peripheral vascular disease. Diabetic peripheral neuropathy is the most common complication of diabetes, affecting ~60% of patients, and is the primary cause of diabetes-related non-traumatic amputations. This condition is the result of microvascular injury of the blood vessels that feed peripheral nerves and is characterized by reductions in nerve conduction velocity, distal motor latency, and reduced nerve fiber density. This report could mean good news for diabetics because current treatment options are mainly limited to pain management.
Sildenafil improves neuropathy in long-term diabetic mice
BKS.Cg-Dock7m +/+ Leprdb/J (000642) mice are frequently used to study diabetes and diabetes-related complications. Leprdb homozygotes (db) display glucose intolerance with chronic hyperglycemia by 8 weeks of age. As the homozygotes age, they develop slowed sensory and motor nerve conduction velocity (SCV and MCV), increased motor latency, and decreased intraepidermal nerve fiber density as compared to non-diabetic control mice. Daily treatment with sildenafil for 8 weeks dramatically improved peripheral neuropathy in BKS.Cg-Dock7m +/+ Leprdb/J middle-aged (36 weeks) homozygous mice. SCV and MCV in the sciatic nerve were both significantly increased as compared to saline treated db mice. Sildenafil treatment also significantly reduced thermal motor latency as measured by plantar and tail flick tests. Blood glucose, A1C, and body weight were unaffected by the sildenafil treatment which indicates that sildenafil does not alleviate peripheral neuropathy by affecting the underlying diabetes.
Sildenafil improves neurovascular function and axonal remodeling
Homozygous db mice display decreased regional blood flow and microvascular perfusion in the sciatic nerve compared to unaffected controls. Db mice treated with sildenafil showed both a substantial increase in blood flow, as measured by laser Doppler flowmetry (LDF), and more extensive microvascularization in the sciatic nerve as compared to saline-treated db controls. The improved neurovascular functions lead to dramatically increased intraepidermal nerve fiber density and enhanced myelin thickness (Figure 1).
In vitro experiments show that high glucose conditions significantly:
- Reduce the ability of endothelial cells to form capillary tubes
- Block neurite outgrowth in DRG neurons
- Inhibit Schwann cell migration
- Reduce levels of Ang1, a soluble protein that promotes neurite growth
Sildenafil reverses these negative effects of high glucose. Blocking the Ang1 receptor, Tie2, with a neutralizing antibody prevents sildenafil from reversing these effects, indicating that sildenafil’s beneficial effects on neurovascular function are mediated by the Ang1/Tie2 signaling pathway.
Collectively, these results demonstrate that sildenafil treatment significantly reduces peripheral neuropathy in mice with long term diabetes and identify sildenafil as a potential therapy for treating diabetic neuropathy.