Therapeutic Benefit of Extended Thymosin β4 Treatment Is Independent of Blood Glucose Level in Mice with Diabetic Peripheral Neuropathy.

Michael Chopp,Longfei Jia,Yi Zhang,Lei Wang,Xuerong Lu,RuiLan Zhang,Alexandra Szalad,Zheng Gang Zhang

doi:10.1155/2015/173656

Michael Chopp, Longfei Jia + Show 6 more

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https://doi.org/10.1155/2015/173656

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Abstract

Peripheral neuropathy is a chronic complication of diabetes mellitus. To investigated the efficacy and safety of the extended treatment of diabetic peripheral neuropathy with thymosin β4 (Tβ4), male diabetic mice (db/db) at the age of 24 weeks were treated with Tβ4 or saline for 16 consecutive weeks. Treatment of diabetic mice with Tβ4 significantly improved motor (MCV) and sensory (SCV) conduction velocity in the sciatic nerve and the thermal and mechanical latency. However, Tβ4 treatment did not significantly alter blood glucose levels. Treatment with Tβ4 significantly increased intraepidermal nerve fiber density. Furthermore, Tβ4 counteracted the diabetes-induced axon diameter and myelin thickness reductions and the g-ratio increase in sciatic nerve. In vitro, compared with dorsal root ganglia (DRG) neurons derived from nondiabetic mice, DRG neurons derived from diabetic mice exhibited significantly decreased neurite outgrowth, whereas Tβ4 promoted neurite growth in these diabetic DRG neurons. Blockage of the Ang1/Tie2 signaling pathway with a neutralized antibody against Tie2 abolished Tβ4-increased neurite outgrowth. Our data demonstrate that extended Tβ4 treatment ameliorates diabetic-induced axonal degeneration and demyelination, which likely contribute to therapeutic effect of Tβ4 on diabetic neuropathy. The Ang1/Tie2 pathway may mediate Tβ4-induced axonal remodeling.

Highlights

Diabetes affects an estimated 346 million people worldwide [1]
We found that extended Thymosin β4 (Tβ4) treatment ameliorates diabetic-induced intraepidermal nerve fiber and sciatic nerve impairment, which likely contributes to functional recovery of diabetic neuropathy
We demonstrate that extended Tβ4 treatment of diabetic mice improves neurological function of diabetic neuropathy, and the improvement is closely associated with amelioration of sciatic nerve axonal and myelin damage and an increase of intraepidermal nerve fiber density

Summary

Introduction

Peripheral neuropathy is a long-term complication of diabetes mellitus which is associated with neurotrophic changes, degeneration, and demyelination of peripheral nerves [2, 3]. There is currently no effective treatment for preventing the development or reversing the progression of diabetic neuropathy. It is imperative to develop therapies for diabetic peripheral neuropathy. Preclinical studies have found that treatment with Tβ4 improves neurological function outcome after central and peripheral nervous system damage [5,6,7]. We previously demonstrated the fact that Tβ4 remarkably improved sciatic nerve vascular function and peripheral nerve function in a model of diabetic peripheral neuropathy [6]. The extended therapeutic effect of Tβ4 on axonal remodeling has not been investigated

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