Role of TPH2 and 5HT Neuronal Loss in Non-motor Symptoms of Parkinson's

项目摘要/摘要 帕金森氏病(PD)是仅次于阿尔茨海默病和 影响约1%的65岁及以上人口。它通常被认为是一种有选择性地针对 破坏多巴胺(DA)神经系统，导致众所周知的运动功能障碍震颤， 运动迟缓、僵硬和姿势不稳。帕金森病的一线药物治疗是L-多巴， 它的目的是补充大脑DA水平，从而显著缓解这些运动 有问题。它没有被广泛认识，但5-羟色胺(5-羟色胺)和去甲肾上腺素(NE)神经元系统是 在帕金森病中也严重降解。虽然如此多的注意力集中在发动机上是恰当的 帕金森病的症状学，根据以下事实，需要对帕金森病的非运动性表现增加兴趣 大约80%的帕金森病患者患有睡眠等共病的神经精神疾病 精神障碍、焦虑和痴呆症。最普遍的情感障碍是抑郁症。非运动性症状 帕金森病(NMS)无论是与疾病进程有关，还是由L-多巴诱导的，都不是微不足道的，都有助于 残疾加剧，生活质量受损，预期寿命缩短。事实上，已经确定 与运动症状相比，帕金森病患者NMS对健康相关生活质量的影响更大。同样明显的是， 帕金森病患者的情感障碍不是简单的心理困扰的结果，这是由于 慢性衰弱疾病。PD的许多NMS可以合理地与PD功能的减少联系起来 5-羟色胺和去甲肾上腺素神经元系统，在治疗NMS时通常遵循的策略加强了这一点。 帕金森病-使用增加这些单胺类突触水平或激活其受体的药物。这些 治疗(即5-羟色胺和去甲肾上腺素转运体的阻滞剂，受体激动剂)并不是很有效，而且在 有些病例甚至反对L多巴的治疗效果。在这一应用中研究的基本原理 首先要认识到，在DA神经元广泛丧失的情况下，5HT和NE的缺乏很可能 为PD的NMS做出贡献。NMS的出现不能用DA的单一损失来解释 帕金森病的神经元。此应用程序中的拟议工作将利用我们实验室中提供的 一种创新的小鼠模型，缺乏色氨酸羟化酶2(TPH2)基因。这款新车型是 用CRE-ERT2-Lox重组方法诱导三苯氧胺后TPH2和5HT的丢失 治疗成年小鼠。5-羟色胺缺陷小鼠将接受1-甲基-4-苯基-1，2，3，6-羟色胺的治疗 四氢吡啶(MPTP)，一种以多巴胺神经元为靶点的神经毒素，和/或与N-(2- (氯乙基)-N-乙基-2-溴苯甲胺(DSP-4)，一种针对NE神经元的高选择性毒素。这个 NMS的出现将通过一系列行为、神经、神经化学和认知评估 测试。此后，单胺缺乏的小鼠将接受L-多巴、L-多巴和/或5-多巴的治疗。 HTP可分别补充脑内DA、NE和5HT的水平。假设PD的NMS出现了 当DA神经元在5-羟色胺和去甲肾上腺素耗竭的背景下丢失时。进一步假设5-羟色胺和 L多巴酚丁胺能有效缓解帕金森病患者的神经系统症状，但不影响L多巴多巴的疗效。 治疗运动障碍。5-羟色胺和L-DOPS分别是5-羟色胺和去甲肾上腺素的氨基酸前体。 已经在许多临床试验中被用于治疗人类。因此，使用它们来降低PD的NMS 代表了一种安全、简单和可转换的方法。

Project Summary/Abstract Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and affects about 1% of the population aged 65 and older. It is often thought of as a condition that selectively targets the dopamine (DA) neuronal system for destruction, giving rise to the well-known motor deficits of tremor, bradykinesia, rigidity and postural instability. The first-line pharmacological treatment for PD is L-DOPA, which is intended to replenish brain DA levels and thereby provide significant relief from these movement problems. It is not widely appreciated but the serotonin (5HT) and norepinephrine (NE) neuronal systems are also severely degraded in PD. While it is appropriate that so much attention is focused on the motor symptomatology of PD, increased interest in non-motor manifestations of PD is called for in light of the fact that approximately 80% of PD patients suffer from co-morbid neuropsychiatric conditions such as sleep disorders, anxiety and dementia. The most prevalent affective disorder is depression. The non-motor symptoms (NMS) of PD, whether related to the disease process or induced by L-DOPA, are not trivial and contribute to worsened disability, impaired quality of life and shortened life expectancy. In fact, it has been determined that NMS of PD have a greater impact on health-related quality of life than motor symptoms. It is also clear that affective disorders in PD are not simply a consequence of psychological distress due to the development of a chronic debilitating disease. Many of the NMS of PD can be rationally linked to reductions in function of the 5HT and NE neuronal systems and this is reinforced by the strategy usually followed when treating the NMS of PD- use of drugs that increase the synaptic levels of these monoamines or that activate their receptors. These treatments (i.e. blockers of the 5HT and NE transporters, receptor agonists) have not been that effective and in some cases, they even oppose the therapeutic efficacy of L-DOPA. The rationale for studies in this application starts with the recognition that 5HT and NE deficits, in the face of extensive losses of DA neurons, likely contribute to the NMS of PD. The appearance of NMS cannot be accounted for by the singular loss of DA neurons in PD. The proposed work in this application will take advantage of the availability in our laboratory of an innovative mouse model that lacks the gene for tryptophan hydroxylase 2 (TPH2). This new model was created using a Cre-ERT2-Lox recombination approach to induce the loss of TPH2 and 5HT after tamoxifen treatment of adult mice. Mice with 5HT deficits will be treated with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), a neurotoxin that targets dopamine neurons for destruction, and/or with N-(2- chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a highly selective toxin that targets NE neurons. The emergence of NMS will be assessed using a battery of behavioral, neurological, neurochemical and cognitive tests. Thereafter, mice lacking the monoamines will be treated with L-DOPA, L-DOPS (Droxidopa) and/or 5- HTP to replenish brain levels of DA, NE and 5HT, respectively. It is hypothesized that the NMS of PD emerge when DA neurons are lost on a background of 5HT and NE depletion. It is further hypothesized that 5-HTP and L-DOPS will effectively relieve the NMS of PD without diminishing the therapeutic efficacy of L-DOPA in treating the motor deficits. 5-HTP and L-DOPS are amino acid precursors to 5HT and NE, respectively, and have been used to treat humans in numerous clinical trials. Therefore, their use to reduce the NMS of PD represents a safe, simple and translational approach.