Mechanisms underlying GLP-1 receptor mediated relief of Parkinson’s disease symptoms

GLP-1 受体介导缓解帕金森病症状的机制

• 批准号: 9765998
• 负责人: Daniel S McGehee
• 金额: $ 44.55万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765998
• 关键词: Acute; Adenylate Cyclase; Affect; Agonist; Animal Model; Basal Ganglia; Brain; Chronic; Clinical Research; Clinical Trials; Corpus striatum structure; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DRD2 gene; Data; Development; Disease Progression; Disease model; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Dyskinetic syndrome; FDA approved; GLP-I receptor; GTP-Binding Protein alpha Subunits, Gs; Goals; Human; Individual; Lesion; Levodopa; Mediating; Mental Depression; Modeling; Motor; Motor output; Movement; Mus; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Output; Parkinson Disease; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Play; Receptor Activation; Replacement Therapy; Reporting; Research; Role; Slice; Substantia nigra structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Viral; dopaminergic neuron; effective therapy; exenatide; experimental study; glucagon-like peptide 1; improved; insight; knock-down; motor control; motor function improvement; motor impairment; motor symptom; mouse model; neuron loss; neuronal excitability; novel; pars compacta; preclinical study; receptor; synaptic function; treatment strategy

Parkinson’s disease (PD) is a progressive neurodegenerative disease leading to motor impairment due to degeneration of nigrostriatal dopaminergic projections. Currently, L-DOPA therapy effectively relieves the motor symptoms in initial stages of PD, however long term treatment with L-DOPA results in loss of efficacy and the development of dyskinesia. Thus, there is a need for other effective therapies for PD. Dopamine in the striatum plays a critical role in modulation of the direct and indirect motor output pathways by activating D1 and D2 receptors in those pathways, respectively. Under normal conditions, dopamine facilitates movement by increasing activity of the direct pathway and decreasing activity of the indirect pathway. In patients with PD, the loss of dopamine results in decreased activity of the direct pathway and increased activity of the indirect pathway. D1 agonists can relieve PD symptoms by increasing cAMP levels and increasing activity of direct pathway medium spiny neurons (MSNs) that express the D1 dopamine receptors. Exenatide, an FDA approved pharmacotherapy commonly prescribed for the treatment of type 2 diabetes, is a glucagon like peptide-1 receptor (GLP-1R) agonist, and a recent clinical trial reported therapeutic benefits of exenatide for PD symptoms. In preclinical studies, GLP-1R agonist treatment has also been shown to protect dopamine neurons from cell death in PD models, but the acute or chronic effects of these receptors on MSN excitability have not been investigated. Our preliminary data suggest that GLP-1Rs are expressed by direct pathway MSNs, and that activation of these receptors increases the excitability of those neurons. As GLP-1R is positively coupled to adenylyl cyclase activity and cAMP levels, the improved motor control in PD patients receiving the GLP-1R agonist may be related to modulatory effects on striatal circuitry. Experiments outlined in this proposal will use a mouse model of PD to examine two aims: The first is to test whether acute GLP-1R agonist exposure can increase intrinsic excitability and corticostriatal synaptic plasticity in striatal MSNs. The second Aim will explore the effects of chronic GLP-1R agonist treatment on motor performance and corticostriatal plasticity of MSNs. These studies will test the hypothesis that GLP-1R agonists may provide alternate treatment strategies for PD symptoms through their effects on striatal circuitry and synaptic plasticity.

帕金森病（PD）是一种进行性神经退行性疾病， 由于黑质纹状体多巴胺能投射的退化而造成的损害。目前，L-DOPA 治疗有效地缓解了运动症状的初始阶段的PD，但长期 用L-DOPA治疗导致功效丧失和运动障碍的发展。因此，在本发明中， 需要其它有效的PD疗法。纹状体中的多巴胺在大脑中 通过激活D1和D2调节直接和间接运动输出通路 分别在这些通路中的受体。在正常情况下，多巴胺有助于 运动通过增加活动的直接途径和减少活动的间接 通路在PD患者中，多巴胺的丧失会导致直接突触活性下降 途径和间接途径的活性增加。D1激动剂可缓解PD症状 通过增加cAMP水平和增加直接通路中棘神经元的活性 （MSNs）表达D1多巴胺受体。一种FDA批准的 通常用于治疗2型糖尿病的药物疗法是胰高血糖素样肽， 肽-1受体（GLP-1 R）激动剂，最近的一项临床试验报告了 帕金森病症状的检查在临床前研究中，GLP-1 R激动剂治疗也被 在PD模型中显示出保护多巴胺神经元免于细胞死亡，但急性或慢性 尚未研究这些受体对MSN兴奋性的影响。我们的初步数据 表明GLP-1 R通过直接途径MSN表达，且这些MSN激活 受体增加了这些神经元的兴奋性。由于GLP-1 R正偶联至 腺苷酸环化酶活性和cAMP水平，PD患者接受 GLP-1 R激动剂可能与对纹状体回路的调节作用有关。实验 本提案中概述的将使用PD小鼠模型来检查两个目标：第一个是测试 急性GLP-1 R激动剂暴露是否可增加内源性兴奋性和皮质纹状体 纹状体MSNs的突触可塑性。第二个目的将探索长期GLP-1 R的作用 激动剂治疗对MSN的运动表现和皮质纹状体可塑性的影响。这些研究 将检验GLP-1 R激动剂可能为PD提供替代治疗策略的假设 通过其对纹状体回路和突触可塑性的影响来缓解症状。