Translational Foundation of Adenosine Antagonist Use for Dyskinesias

腺苷拮抗剂用于治疗运动障碍的转化基础

• 批准号: 7590277
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 35.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590277
• 关键词: Adenosine; Adenosine A2A Receptor; Agonist; Air; Antiparkinson Agents; Attenuated; Behavior; Behavioral; Brain; Clinical; Clinical Data; Clinical Trials; Complex; Corpus striatum structure; DRD2 gene; Dependence; Development; Disadvantaged; Disease; Dopamine Receptor; Dose; Dynorphins; Dyskinetic syndrome; Enkephalins; Foundations; G Protein-Coupled Receptor Genes; GRM5 gene; Genes; Genetic; Knock-out; Knowledge; L-DOPA induced dyskinesia; Lesion; Letters; Levodopa; Link; Maintenance; Modeling; Molecular; Motor; Motor Activity; Mus; Neurobiology; Neuronal Plasticity; Neurons; Output; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Patients; Phase; Play; Prevention; Primates; Process; Prosencephalon; Purinergic P1 Receptors; Recommendation; Relative (related person); Research Personnel; Rodent; Role; Signal Transduction; System; Testing; Therapeutic; Time; Translating; United States National Institutes of Health; base; behavioral sensitization; design; disability; experience; improved; insight; mouse model; neurotransmission; nonhuman primate; novel; postnatal; pre-clinical; prevent; programs; receptor; receptor function; response

DESCRIPTION (provided by applicant): The adenosine A2A receptor (A2AR) has emerged as a promising target for Parkinson's disease (PD) therapy based on its ability to modulate dopaminergic neurotransmission and its remarkably discrete localization to a subset of striatal output neurons. Preclinical evidence that A2A antagonists reliably reduce motor disability without producing dyskinesias (motor complications of standard L-dopa therapy) in parkinsonian primates has led to encouraging initial clinical data on A2A antagonists in advanced PD patients already experiencing dyskinesias. However, little is known about the role of A2ARs in the maladaptive neuroplasticity underlying the development of L-dopa-induced dyskinesias (LID). We and others have demonstrated that A2AR inactivation can prevent or reverse sensitized motor responses to repeated L- dopa administration in rodent and primate models of dyskinesias. Here in response to NIH PAS-02-129 we propose to systematically investigate A2AR involvement in the maladaptive neuroplasticity of a mouse model of LID. Using complementary genetic (constitutive and brain-specific conditional knockout) and classical pharmacological approaches to adenosine (At and A2A) receptor inactivation, we will systematically pursue 3 specific aims: 1) To determine the adenosinergic (A1 and A2A) contributions to L-dopa sensitization in hemiparkinsonian (6-OHDA-lesioned) mice. 2) To determine whether A2A antagonists reduce L-dopa- induced behavioral sensitization by preventing its induction, maintenance and/or expression. 3) To explore how the A2AR interacts with its dopaminergic and heteromeric GPCR partners (D1, D2 and mGluS receptors) in modulating L-dopa sensitization. We will also assess the role of adenosine receptors in molecular adaptations linked to dyskinesias, including changes in striatal expression of dynorphin, enkephalin and the A2AR itself. Relevance: In addition to providing fundamental insights into adenosine neurobiology, the proposal is designed to yield practical knowledge of adenosine receptor function in a model of the dyskinesias that complicate standard antiparkinsonian treatments. The translational potential and efficiency of the project will be further enhanced by coordinating its ongoing findings with parallel non-human primate and clinical programs currently pursuing the therapeutic benefits of A2A antagonists for PD.

描述（由申请人提供）：腺苷A2A受体（A2AR）基于调节多巴胺能神经传递的能力及其对纹状体输出神经元子集的显着分散位置，成为帕金森氏病（PD）治疗的有希望的靶标。临床前证明A2A拮抗剂可靠地减少运动障碍，而不会产生帕金森氏症灵长类动物中的运动障碍（标准L-DOPA疗法的运动并发症（标准L-DOPA疗法的运动并发症），导致鼓励已经患有患者的高级PD患者的A2A拮抗剂的初步临床数据。然而，关于A2AR在L-DOPA诱导的运动障碍（LID）发展的不良神经塑性中的作用知之甚少。我们和其他人已经证明，在啮齿动物和灵长类动物学模型中，A2AR灭活可以防止或反向对重复的L-多帕给药的运动反应。在此响应NIH PAS-02-129时，我们建议系统地研究A2AR对盖子模型的适应不良神经塑性的参与。使用补充遗传（本构和脑特异性条件敲除）和经典的腺苷药理学方法（AT和A2A）受体失活，我们将系统地追求3个具体目的：1）确定对L-DOPA的腺苷能（A1和A2A）的贡献在半钙素（6- ohda剂量）小鼠中的敏化。 2）确定A2A拮抗剂是否通过防止其诱导，维护和/或表达来减少L-dopa诱导的行为敏化。 3）探索A2AR如何与其多巴胺能和异源GPCR伙伴（D1，D2和MGLUS受体）相互作用，以调节L-DOPA敏感性。我们还将评估腺苷受体在与运动障碍相关的分子适应性中的作用，包括纹状phin，Enkephalin和A2AR本身的纹状体表达变化。相关性：除了对腺苷神经生物学提供基本见解外，该提案旨在在使标准的反帕金森氏疗法复杂化的动态障碍模型中产生腺苷受体功能的实际知识。该项目的转化潜力和效率将通过与平行的非人类灵长类动物和临床计划进行协调，从而进一步提高，目前追求A2A拮抗剂对PD的治疗益处。