Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 54538, Korea.
Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX 77555-0625, USA.
Int J Mol Sci. 2022 Feb 21;23(4):2388. doi: 10.3390/ijms23042388.
Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve motor symptoms and do not treat the cause of the disease, highly effective drugs are needed. Vildagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, is an anti-diabetic drug with various pharmacological properties including neuroprotective effects. However, the detailed effects of vildagliptin against PD are not fully understood. We investigated the effects of vildagliptin on PD and its underlying molecular mechanisms using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and a 1-methyl-4-phenylpyridium (MPP)-induced cytotoxicity model. Vildagliptin (50 mg/kg) administration significantly attenuated MPTP-induced motor deficits as evidenced by rotarod, pole, and nest building tests. Immunohistochemistry and Western blot analysis revealed that vildagliptin increased tyrosine hydroxylase-positive cells in the SNpc and striatum, which was reduced by MPTP treatment. Furthermore, vildagliptin activated MPTP-decreased PI3k/Akt and mitigated MPTP-increased ERK and JNK signaling pathways in the striatum. Consistent with signaling transduction in the mouse striatum, vildagliptin reversed MPP-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP-induced conversion of LC3B-II in SH-SY5Y cells, suggesting its role in autophagy inhibition. Taken together, these findings indicate that vildagliptin has protective effects against MPTP-induced motor dysfunction by inhibiting dopaminergic neuronal apoptosis, which is associated with regulation of PI3k/Akt, ERK, and JNK signaling transduction. Our findings suggest vildagliptin as a promising repurposing drug to treat PD.
帕金森病（PD）的特征是中脑黑质致密部（SNpc）中的多巴胺能神经元丧失。恢复黑质纹状体多巴胺神经元被认为是 PD 的一种潜在治疗策略。由于目前使用的 PD 治疗药物仅有助于缓解运动症状，而不能治疗疾病的原因，因此需要高度有效的药物。维格列汀是一种二肽基肽酶 4（DPP4）抑制剂，是一种具有多种药理特性的抗糖尿病药物，包括神经保护作用。然而，维格列汀对 PD 的详细作用尚不完全清楚。我们使用 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠模型和 1-甲基-4-苯基吡啶（MPP）诱导的细胞毒性模型研究了维格列汀对 PD 的作用及其潜在的分子机制。维格列汀（50mg/kg）给药显著减轻了 MPTP 诱导的运动缺陷，如旋转棒、杆和巢筑测试。免疫组织化学和 Western blot 分析显示，维格列汀增加了 SNpc 和纹状体中酪氨酸羟化酶阳性细胞，而这些细胞在 MPTP 处理后减少。此外，维格列汀激活了 MPTP 降低的 PI3k/Akt 信号通路，并减轻了 MPTP 增加的 ERK 和 JNK 信号通路在纹状体中的作用。与小鼠纹状体中的信号转导一致，维格列汀逆转了 MPP 诱导的 SH-SY5Y 细胞中 PI3k/Akt 的去磷酸化和 ERK 和 JNK 的磷酸化。此外，维格列汀减弱了 MPP 诱导的 SH-SY5Y 细胞中 LC3B-II 的转化，表明其在自噬抑制中的作用。综上所述，这些发现表明维格列汀通过抑制多巴胺能神经元凋亡对 MPTP 诱导的运动功能障碍具有保护作用，这与 PI3k/Akt、ERK 和 JNK 信号转导的调节有关。我们的研究结果表明，维格列汀作为一种有前途的重新利用药物，可用于治疗 PD。
