Liu Wen-Hong, Liu Cui, Xue Yan, Sun Xiang-Rong, Chen Xin-Yi, Chen Lei
Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China.
Department of Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical, Jinan, China.
Front Aging Neurosci. 2025 Apr 25;17:1529919. doi: 10.3389/fnagi.2025.1529919. eCollection 2025.
The gradual decline of nigral dopaminergic neurons is the main cause of Parkinson's disease (PD), yet as of now, there exists no conclusive therapeutic intervention. Glucagon-like peptide-1 (GLP-1) is an incretin, which is also a key substance regulating neuronal activity and synaptic transmission. GLP-1 receptors (GLP-1Rs) are widely expressed in the central nervous system. Chronic administration of low doses of 1-methyl-4-phenyl, 1,2,3,6-tetrahydropiridine (MPTP) mitigates mortality in mice during the modeling phase, thereby more closely mirroring the progression of PD. This study aims to observe the effects of GLP-1 receptor agonists (GLP-1RAs) on the firing activity of nigral dopaminergic neurons and motor behaviors in MPTP-induced chronic PD mice. Our findings revealed that peripheral administration of GLP-1RAs exendin-4 significantly alleviated motor impairments in MPTP-induced chronic PD mice. Concurrently, peripheral administration of exendin-4 increased the number of active dopaminergic neurons, improved the spontaneous firing activity, as well as alleviated MPTP-induced dopaminergic neuron loss in MPTP-induced PD mice. Furthermore, local administration of exendin-4 directly increased the firing rate of nigral dopaminergic neurons via GLP-1Rs, suggesting that peripheral administration of exendin-4 may exert neuroprotection through its mild excitation on dopaminergic neurons. These findings collectively imply that peripheral administration of GLP-1RAs may hold potential in the treatment of PD.
黑质多巴胺能神经元的逐渐衰退是帕金森病（PD）的主要病因，但截至目前，尚无确凿的治疗干预措施。胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素，也是调节神经元活动和突触传递的关键物质。GLP-1受体（GLP-1Rs）在中枢神经系统中广泛表达。长期低剂量给予1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）可降低小鼠建模阶段的死亡率，从而更接近地反映PD的进展情况。本研究旨在观察GLP-1受体激动剂（GLP-1RAs）对MPTP诱导的慢性PD小鼠黑质多巴胺能神经元放电活动及运动行为的影响。我们的研究结果显示，外周给予GLP-1RAs艾塞那肽-4可显著减轻MPTP诱导的慢性PD小鼠的运动障碍。同时，外周给予艾塞那肽-4可增加活性多巴胺能神经元的数量，改善自发放电活动，并减轻MPTP诱导的PD小鼠中MPTP引起的多巴胺能神经元损失。此外，局部给予艾塞那肽-4可通过GLP-1Rs直接提高黑质多巴胺能神经元的放电频率，这表明外周给予艾塞那肽-4可能通过对多巴胺能神经元的轻度兴奋发挥神经保护作用。这些研究结果共同表明，外周给予GLP-1RAs可能在PD治疗中具有潜力。
