Beneficial Effects of Exendin-4 on Experimental Polyneuropathy in Diabetic Mice

• DOI: 10.2337/db10-1462
• Publication Date: 2011-08-02T04:22:29Z
• Authors: Tatsuhito Himeno; Hideki Kamiya; Keiko Naruse; Norio Harada; Nobuaki Ozaki; Yusuke Seino; Taiga Shibata; Masaki Kondo; Jiro Kato; Tetsuji Okawa; Ayako Fukami; Yoji Hamada; Nobuya Inagaki; Yutaka Seino; Daniel J. Drucker; Yutaka Oiso; Jiro Nakamura
• Keywords: Male; 0301 basic medicine; Complications; Venoms; Neural Conduction; Sciatic Nerve; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Experimental; 3. Good health; Mice; 03 medical and health sciences; Diabetic Neuropathies; Ganglia, Spinal; Receptors, Glucagon; Animals; Exenatide; Hypoglycemic Agents; Schwann Cells; Peptides

OBJECTIVE The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated.

RESEARCH DESIGN AND METHODS The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell–conditioned media in the presence or absence of GLP-1 (7–37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated.

RESULTS The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7–37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell–conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA1c levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4.

CONCLUSIONS Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.