NOVEL BENEFIT OF A2A RECEPTOR INACTIVATION IN PD MODELS

描述：(改编自申请者摘要)帕金森氏症 患者经历纹状体多巴胺(DA)严重耗竭，原因是 黑质纹状体DA通路变性。本病的主要治疗方法 过去30年一直是DA的前身，L-多巴。在这个策略改进的同时 运动障碍，它对潜在的退变过程没有影响，并且 确实可能会产生额外的不良副作用，导致运动障碍。一个 可能的替代疗法，具有神经保护能力，似乎是使用 一种特定类型的腺苷受体的拮抗剂，A2a。这些特工 似乎既有运动激活特性，也有初步数据表明 它们还可以减轻MPTP诱导的DA神经毒性，阻止运动 与慢性DA受体刺激一起发生的刺激。建议数 研究将系统地研究新型运动和神经保护 A2a受体拮抗剂的作用。方法以药理学为中心 研究和使用基因敲除(KO)方法。有三个具体的 目的：1)检验A2A失活增强运动功能的假说 通过D2R依赖和独立的机制使用A2AR-KO、D2R-KO和 双KO小鼠；2)检验A2AR失活阻止 L多巴慢性旋转运动敏感化动物模型的研究进展 单侧6-OHDA损毁小鼠；3)研究V在脑内的作用。 MPTP所致神经毒性的“治疗窗”效应 并通过“分析A2AR激活和失活之间的协同作用；” 此外，A2AR制剂对MPTP体内和细胞内代谢的影响 培养也将被检查以研究神经化学机制。 通过A2AR失活来保护。

DESCRIPTION: (Adapted from the Applicant's Abstract) Parkinson's disease patients experience profound depletion of striatal dopamine (DA) due to degeneration of the nigrostriatal DA pathway. The predominant treatment for the past 30 years has been the DA precursor, L-dopa. While this strategy improves motor deficits, it has no effect on the underlying degenerative process, and indeed can have the additional unwanted side-effect of inducing dyskinesia. A possible alternative therapy, with neuroprotective ability appears to be use of antagonists of a specific class of adenosine receptors, A2A. These agents appear to have both motor-activating properties and preliminary data suggest they may also attenuate MPTP-induced DA neurotoxicity and prevent the locomotor stimulation that occurs with chronic DA receptor stimulation. The proposed studies will systematically investigate the novel motor and neuroprotective effects of A2A receptor antagonists. Methods center around pharmacological studies and use of genetic knockout (KO) approaches. There are three specific aims: 1) to test the hypothesis that A2A inactivation enhances motor function through D2R-dependent and independent mechanisms using A2AR-KO, D2R-KO and double KO mice; 2) to test the hypothesis that A2AR inactivation prevents the development of chronic L-dopa-induced rotational motor sensitization in unilateral 6-OHDA-lesioned mice; and 3) to characterize the role of V in MPTP-induced neurotoxicity by establishing the potency, "therapeutic window" and by "analyzing synergy between A2AR activation and inactivation;" in addition, the effect of A2AR agents on MPTP metabolism in vivo and in cell culture will also be examined to investigate the neurochemical mechanisms of protection by A2AR inactivation.