Abstract
We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 20 weeks were treated with tadalafil every 48 hours for 8 consecutive weeks. Compared with diabetic mice treated with saline, tadalafil treatment significantly improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity. Tadalafil treatment also markedly increased local blood flow and the density of FITC-dextran perfused vessels in the sciatic nerve concomitantly with increased intraepidermal nerve fiber density. Moreover, tadalafil reversed the diabetes-induced reductions of axon diameter and myelin thickness and reversed the diabetes-induced increased g-ratio in the sciatic nerve. Furthermore, tadalafil enhanced diabetes-reduced nerve growth factor (NGF) and platelet-derived growth factor-C (PDGF-C) protein levels in diabetic sciatic nerve tissue. The present study demonstrates that tadalafil increases regional blood flow in the sciatic nerve tissue, which may contribute to the improvement of peripheral nerve function and the amelioration of diabetic peripheral neuropathy.
Highlights
Phosphodiesterase-5 (PDE5) is highly specific for hydrolysis of cyclic nucleotides monophosphate
Tadalafil improves neurological function in the diabetic mouse To examine the effect of tadalafil on diabetic peripheral neuropathy, diabetic db/db mice at aged 20 weeks, which exhibited severe peripheral nerve neurological deficits, were orally (p.o.) administered with tadalafil at a dose of 10 mg/kg every 48 hours for 8 consecutive weeks
Tadalafil treatment significantly improved diabetic-reduced motor and sensory conduction velocity (MCV and sensory nerve conduction velocity (SCV)) in the sciatic nerve measured by electrophysiological tests, while significant improvements of sensory function as measured by Plantar and Tail-Flick tests were evident starting at 6 weeks after the initial treatment compared with saline–treated diabetic mice (Fig 1)
Summary
Phosphodiesterase-5 (PDE5) is highly specific for hydrolysis of cyclic nucleotides monophosphate (cGMP). PDE5 inhibitors are primarily used as pharmacological agents for the treatment of erectile dysfunction (ED) and pulmonary hypertension [1,2,3]. Peripheral neuropathy is a chronic complication of diabetes. Human and experimental studies have demonstrated that the PDE5 inhibitor, sildenafil, reduces symptoms of peripheral neuropathy [4, 5]. PLOS ONE | DOI:10.1371/journal.pone.0159665 July 20, 2016
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