Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD.

流行病学研究报告称，2 型糖尿病 (T2DM) 患者患帕金森病 (PD) 的风险较高，服用二肽基肽酶 4 (DPP-4) 抑制剂可减轻这种风险。为了在充分表征的 PD 啮齿动物模型中表征 DPP-4 抑制剂（格列汀）的临床可转化剂量，在给药前 7 天或给药后 7 天对大鼠口服西他列汀、PF-00734,200 或载体单侧内侧前脑束 6-羟基多巴胺 (6-OHDA) 损伤。此后评估同侧和对侧大脑中多巴胺能细胞活力、多巴胺含量、神经炎症和神经发生的测量。对血浆和脑肠促胰岛素和 DPP-4 活性水平进行定量。此外，在啮齿动物、6-OHDA 攻击的动物和患有/不患有 PD 的人类受试者中，对大脑肠促胰岛素受体水平进行了年龄依赖性评估。细胞研究评估了联合肠降血糖素给药的神经营养/神经保护作用。口服西他列汀或 PF-00734,200 预处理可减少甲基苯丙胺 (meth) 诱导的损伤后旋转以及病变黑质致密部 (SNc) 和纹状体中的多巴胺能变性。直接脑室内给予格列汀缺乏神经保护作用，表明全身肠促胰岛素介导的机制支撑着格列汀诱导的有利脑效应。同样，用三倍高的口服格列汀剂量进行后治疗，减轻了甲基苯丙胺引起的旋转、多巴胺能神经变性和神经炎症，并增强了神经发生。这些格列汀诱导的作用与 70-80% 血浆和 20-30% 脑 DPP-4 抑制以及血浆和脑肠促胰岛素水平升高相关。啮齿类动物、接受 6-OHDA 攻击的大鼠以及患有 PD 的人类中，大脑肠促胰素受体蛋白水平保持与年龄相关。在神经元培养物中联合激活 GLP-1 和 GIP 受体可产生优于单独使用单一激动剂的神经营养/神经保护作用。总之，这些研究支持进一步评估临床批准的格列汀作为帕金森病治疗策略的重新用途。