Pathophysiology and therapeutic testing in a new monkey model of parkinsonism

描述(由申请人提供)：帕金森氏病(PD)治疗的合理改进和针对性将通过分析疾病的病理特征和症状之间的关系的能力来促进。然而，神经毒素模型在将疾病分解为其组成部分特征方面的能力有限。这一问题因两种日益受到重视的并发症而加剧：1)多巴胺(DA)的丢失绝不限于特发性帕金森病或该病的神经毒素模型中的纹状体；2)单个DA神经元支配多个大脑区域。我们提出了一个猴子模型来研究帕金森症的病理基础，克服了这些并发症带来的障碍。可逆性脑内阻断DA神经传递可精确控制DA丢失/阻断的位置、空间范围和严重程度以及时间进程。正是DA功能障碍的这些方面，即使不是不可能，也很难使用神经毒素来控制。拟议的实验将使用DA拮抗剂来解决中央但持久的问题，即纹状体中DA的丢失是否会产生帕金森病的主要症状。虽然运动障碍、运动迟缓、震颤和僵直通常归因于纹状体DA的丢失，但特发性帕金森病和神经毒素诱导的帕金森病也以其他结构的DA丢失为标志。第一个目标将确定这些体征是否可以通过短暂拮抗运动纹状体中的DA受体(包括d1和d2)在灵长类动物身上重现。对流增强递送将用于在后壳核(特发性帕金森病中DA丢失最严重的部位)的重要部分产生DA受体的均匀阻断。帕金森症患者的体征将使用旨在操纵相关行为参数的任务来测量：运动启动/排序(运动迟缓)、运动运动学(运动迟缓)、震颤和肌肉张力(僵直)。苍白球内侧是将帕金森病患者的DA功能障碍转化为帕金森症状的关键环节。第二个目标将确定苍白球神经元放电的哪些异常可以直接归因于纹状体DA的丢失，从而导致所引起的损害。这一目标还将使苍白球放电的特定异常与特定帕金森症状的出现相关联。公共卫生相关性：尽管帕金森氏症在人群中的流行率越来越高，但由于我们对疾病的病理(即哪些细胞死亡)与其症状之间的关系的基本了解，新治疗方法的改进和准确的解剖学靶向受到阻碍。这里提出的动物模型和实验将为引起帕金森症状的关键病理缺陷提供重要的新信息。新的细胞和基因疗法的靶点选择将以这些信息为指导。

DESCRIPTION (provided by applicant): Rational refinement and targeting of therapies for Parkinson's disease (PD) will be facilitated by an ability to analyze relationships between the pathologic features of the disease and symptoms. Neurotoxin models, however, are limited in their ability to break down the disease into its component features. This problem is exacerbated by two complications that are coming to greater recognition: 1) loss of dopamine (DA) is by no means restricted to the striatum in idiopathic PD or in neurotoxin models of the disease; and 2) individual DA neurons innervate multiple brain regions. We propose a monkey model for studying the pathologic underpinnings of parkinsonism that overcomes the hurdles presented by these complications. Reversible intracerebral blockade of DA neurotransmission will afford precise control over the location of DA loss/blockade, its spatial extent and severity, and its timecourse. It is precisely these aspects of DA dysfunction that are difficult if not impossible to control using neurotoxins. The proposed experiments will use DA antagonists to address the central, yet persistent, question whether loss of DA from the striatum alone can generate the cardinal signs of PD. Although akinesia, bradykinesia, tremor and rigidity are commonly attributed to striatal loss of DA, idiopathic PD and neurotoxin-induced parkinsonism are marked by DA loss in other structures as well. The first aim will determine if these signs can be reproduced in primates by transient antagonism of DA receptors (both D1 and D2) in the motor striatum. Convection-enhanced delivery will be used to produce a homogeneous blockade of DA receptors within significant portions of the posterior putamen (site of the most severe DA loss in idiopathic PD). Parkinsonian signs will be measured using tasks designed to manipulate relevant behavioral parameters: movement initiation/sequencing (akinesia), movement kinematics (bradykinesia), tremor, and muscle tone (rigidity). The internal globus pallidus is a critical link in the translating the DA dysfunction of PD into parkinsonian signs. The second aim will determine which abnormalities in the firing of globus pallidus neurons can be attributed directly to the loss of striatal DA and thus contribute to the impairments elicited. This aim will also correlate specific abnormalities in pallidal firing with the appearance of specific parkinsonian symptoms. PUBLIC HEALTH RELEVANCE: Despite the growing prevalence of Parkinson's disease in the population, refinement and accurate anatomical targeting of new treatments is impeded by our rudimentary understanding of the relationship between the pathology of the disease (i.e., which cells die) and its symptoms. The animal model and experiments proposed here will provide important new information about the critical pathologic defects that give rise to parkinsonian signs. Target selection for new cell and gene therapies will be guided by this information.