Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Int J Mol Sci. 2021 Mar 15;22(6):2971. doi: 10.3390/ijms22062971.
Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron-IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.
除了对胰岛β细胞的胰岛素样作用外，胰高血糖素样肽-1（GLP-1）的神经保护作用也引起了关注。GLP-1 受体（GLP-1R）激动剂 exendin-4（Ex-4）已被报道可用于坐骨神经损伤后的功能修复和改善糖尿病周围神经病变（DPN）；然而，其潜在机制尚不清楚。在这项研究中，研究了 Ex-4 对永生化成年大鼠许旺细胞 IFRS1 和成年大鼠背根神经节（DRG）神经元-IFRS1 共培养系统的生物活性。使用经敲除验证的单克隆抗体 Mab7F38 证实了 GLP-1R 在 DRG 神经元和 IFRS1 细胞中的定位。用 100 nM Ex-4 处理可显著增强 IFRS1 细胞的存活/增殖和迁移，并刺激 IFRS1 细胞向共培养中 DRG 神经元胞体发出的轴突突起移动，同时上调髓鞘蛋白 22 和髓鞘蛋白零。因为 Ex-4 在这些细胞中诱导丝氨酸/苏氨酸特异性蛋白激酶 AKT 的磷酸化，并且其对 DRG 神经元和 IFRS1 细胞的作用被磷脂酰肌醇-3'-磷酸激酶（PI3K）抑制剂 LY294002 减弱，Ex-4 可能作用于这两种细胞以激活 PI3K/AKT 信号通路，从而促进共培养中的髓鞘形成。这些发现暗示了 Ex-4 对 DPN 和其他周围神经病变的潜在疗效。
