Pathophysiology and therapeutic testing in a new monkey model of parkinsonism

描述（由申请人提供）：通过分析疾病病理特征和症状之间的关系，将有助于合理改进和靶向治疗帕金森病（PD）。然而，神经毒素模型在将疾病分解为其组成特征方面的能力是有限的。这一问题因两种越来越受到重视的并发症而加剧：1)在特发性PD或该疾病的神经毒素模型中，多巴胺（DA）的丧失绝不仅限于纹状体；2)单个DA神经元支配多个脑区。我们提出了一个猴子模型来研究帕金森病的病理基础，克服了这些并发症带来的障碍。DA神经传递的可逆脑内阻断可以精确控制DA丢失/阻断的位置、空间范围和严重程度以及时间进程。正是这些方面的DA功能障碍是很难，如果不是不可能控制使用神经毒素。拟议的实验将使用DA拮抗剂来解决一个核心的，但持久的问题，即纹状体中DA的丧失是否会产生PD的主要症状。虽然运动障碍、运动迟缓、震颤和强直通常归因于纹状体DA丢失，但特发性PD和神经毒素诱导的帕金森病也以其他结构的DA丢失为特征。第一个目的是确定这些信号是否可以通过运动纹状体中DA受体（D1和D2）的短暂拮抗在灵长类动物中重现。对流增强给药将用于在后壳核（特发性PD中DA损失最严重的部位）的显著部分内对DA受体产生均匀的阻断。帕金森症状的测量将使用旨在操纵相关行为参数的任务：运动启动/排序（运动障碍）、运动运动学（运动迟缓）、震颤和肌肉张力（僵硬）。内部苍白球是PD的DA功能障碍转化为帕金森症状的关键环节。第二个目标是确定苍白球神经元放电中的哪些异常可以直接归因于纹状体DA的丧失，从而导致所引起的损伤。这一目的还将把苍白质放电的特定异常与特定帕金森症状的出现联系起来。公共卫生相关性：尽管帕金森氏病在人群中越来越流行，但我们对疾病病理（即哪些细胞死亡）与症状之间关系的基本理解阻碍了新的治疗方法的完善和准确的解剖学目标。本文提出的动物模型和实验将提供有关导致帕金森症状的关键病理缺陷的重要新信息。新的细胞和基因疗法的靶标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.