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，会导致运动障碍 由于黑质纹状体多巴胺能投射退化而导致的损害目前，左旋多巴。 治疗可有效缓解帕金森病初始阶段的运动症状，但从长远来看 用左旋多巴治疗会导致疗效丧失和运动障碍的发生。 纹状体中的多巴胺发挥着关键作用，因此需要其他有效的治疗方法。 通过激活 D1 和 D2 在调节直接和间接运动输出通路中的作用 在正常情况下，多巴胺分别促进这些途径中的受体。 通过增加直接途径的活动和减少间接途径的活动来运动 在 PD 患者中，多巴胺的丧失会导致直接神经元的活性降低。 途径和增加间接途径的活性可以缓解 PD 症状。 通过增加 cAMP 水平和增加直接通路中型多棘神经元的活性 （MSN）表达 D1 多巴胺受体，艾塞那肽是 FDA 批准的药物。 通常用于治疗 2 型糖尿病的药物疗法是一种类似胰高血糖素的药物 肽-1 受体 (GLP-1R) 激动剂，最近的一项临床试验报告了其治疗益处 在临床前研究中，艾塞那肽也用于治疗 PD 症状。 在 PD 模型中显示可保护多巴胺神经元免于细胞死亡，但急性或慢性 我们的初步数据尚未研究这些受体对 MSN 兴奋性的影响。 表明 GLP-1R 由直接途径 MSN 表达，并且这些 MSN 的激活 由于 GLP-1R 与 GLP-1R 呈正耦合，因此 GLP-1R 受体会增加这些神经元的兴奋性。 腺苷酸环化酶活性和 cAMP 水平，改善 PD 患者的运动控制 GLP-1R 激动剂可能与纹状体电路的调节作用有关。 该提案中概述的将使用 PD 小鼠模型来检查两个目的：第一个是测试 急性 GLP-1R 激动剂暴露是否会增加内在兴奋性和皮质纹状体 第二个目标将探讨慢性 GLP-1R 的影响。 激动剂治疗对 MSN 运动性能和皮质纹状体可塑性的影响。 将检验 GLP-1R 激动剂可能为 PD 提供替代治疗策略的假设 通过对纹状体回路和突触可塑性的影响来观察症状。