NOVEL BENEFIT OF A2A RECEPTOR INACTIVATION IN PD MODELS

描述：（改编自申请人的摘要）帕金森病 患者经历纹状体多巴胺（DA）的严重耗竭， 黑质纹状体DA通路的退化。主要的治疗方法是 是多巴胺的前体左旋多巴虽然这一战略改善了 运动缺陷，对潜在的退行性过程没有影响， 实际上可能具有诱发运动障碍的额外的不希望的副作用。一 可能的替代疗法，具有神经保护能力，似乎是使用 腺苷受体A2 A的拮抗剂。这些试剂 似乎具有运动激活特性，初步数据表明， 它们还可以减弱MPTP诱导的DA神经毒性， 慢性DA受体刺激时发生的刺激。拟议 研究将系统地调查新的运动和神经保护 A2 A受体拮抗剂的作用方法围绕药理学 研究和使用基因敲除（KO）方法。有三个具体的 目的：1）验证A2 A失活增强运动功能的假设 通过使用A2 AR-KO、D2 R-KO和 双KO小鼠; 2）为了检验A2 AR失活阻止了 慢性左旋多巴诱导的旋转运动致敏作用的发展 单侧6-OHDA损伤的小鼠;和3）表征V在 通过建立效价、“治疗窗”来确定MPTP诱导的神经毒性 和通过“分析A2 AR激活和失活之间的协同作用”; 此外，A2 AR剂对体内和细胞中MPTP代谢的影响也被研究。 文化也将被检查，以调查的神经化学机制， A2 AR失活保护。

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.