Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Diabetes. 2011 Sep;60(9):2397-406. doi: 10.2337/db10-1462. Epub 2011 Aug 1.
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.
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.
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 HbA(1c) 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.
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.
研究胰高血糖素样肽-1 受体（GLP-1R）激动剂 exendin-4 对链脲佐菌素（STZ）诱导的糖尿病小鼠糖尿病多发性神经病（DPN）的治疗潜力。
通过免疫组织化学分析评估腰椎背根神经节（DRG）中 GLP-1R 的存在。从 C57BL6/J 小鼠中分离 DRG 神经元，并在有或没有 Schwann 细胞条件培养基的情况下，与 GLP-1（7-37）或 exendin-4 一起培养，然后测定神经突生长。在动物模型实验中，通过 STZ 给药使小鼠发生糖尿病，在糖尿病 12 周后，每天腹腔内给予 exendin-4（10 nmol/kg）一次，共 4 周。通过电流感知阈值和运动及感觉神经传导速度（MNCV 和 SNCV）来确定周围神经功能。还评估坐骨神经血流（SNBF）和表皮内神经纤维密度（IENFDs）。
证实了 DRG 神经元中 GLP-1R 的表达。GLP-1（7-37）和 exendin-4 显著促进 DRG 神经元的神经突生长。两种 GLP-1R 激动剂均加速了模拟糖尿病条件的 Schwann 细胞条件培养基培养的 DRG 神经元受损的神经突生长。在使用的剂量下，exendin-4 对血糖或 HbA（1c）水平没有影响。exendin-4 改善了糖尿病小鼠的痛觉过敏和运动及感觉神经传导速度的延迟，而不影响减少的 SNBF。exendin-4 改善了糖尿病小鼠足底皮肤中减少的 IENFDs。
我们的研究结果表明，exendin-4 可改善 DPN 的严重程度，这可能是通过其对 DRG 神经元及其轴突的直接作用实现的。
