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

帕金森病(PD)是一种进行性神经退行性疾病，导致运动 黑质纹状体多巴胺能投射变性所致的损害。目前，L-多巴 治疗能有效缓解帕金森病初期的运动症状，不管是长期的 使用L多巴治疗会导致疗效丧失和运动障碍的发展。因此， 帕金森病需要其他有效的治疗方法。纹状体中的多巴胺起着关键的作用 激活d1和d2在调节直接和间接运动输出通路中的作用 分别在这两条通路中的受体。在正常情况下，多巴胺有助于 通过增加直接通路的活动和减少间接途径的活动来运动 路径。在帕金森病患者中，多巴胺的丧失会导致直接的 间接途径的活性增加。D1激动剂可缓解帕金森病症状 通过增加cAMP水平和增加直接通路中棘神经元的活性 (MSN)表达D1多巴胺受体。美国食品和药物管理局批准的艾塞那肽 通常用于治疗2型糖尿病的药物疗法是一种类似于胰高血糖素的药物 多肽-1受体(GLP-1R)激动剂，最近的一项临床试验报告了治疗效果 艾塞那肽治疗帕金森病症状。在临床前研究中，GLP-1R激动剂的治疗也 显示在帕金森病模型中保护多巴胺神经元免受细胞死亡，但急性或慢性 这些受体对MSN兴奋性的影响尚未被研究。我们的初步数据 提示GLP-1Rs通过直接途径MSN表达，并激活这些MSN 受体增加了这些神经元的兴奋性。因为GLP-1R正耦合到 腺苷环化酶活性和cAMP水平，改善帕金森病患者的运动控制 GLP-1R激动剂可能与纹状体回路的调节作用有关。实验 在这份提案中概述将使用小鼠模型来检验帕金森病有两个目的：一是测试 急性GLP-1R激动剂暴露是否会增加内源性兴奋性和皮质纹状体 纹状体MSN的突触可塑性。第二个目标将探索慢性GLP-1R的影响 激动剂治疗对MSN运动能力和皮质纹状体可塑性的影响。这些研究 将检验GLP-1R激动剂可能为帕金森病提供替代治疗策略的假设 症状通过它们对纹状体回路和突触可塑性的影响。

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.