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

TPH2 和 5HT 神经元丢失在帕金森病非运动症状中的作用

• 批准号: 9191887
• 负责人: Donald M Kuhn
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191887
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 5-Hydroxytryptophan; Accounting; Achievement; Adult; Affect; Agonist; Alzheimer' s Disease; Amino Acids; Animal Model; Anxiety; Appearance; Attention; Behavioral; Body Weight; Bradykinesia; Brain; Cell Nucleus; Cells; Chronic; Clinical Trials; Combined Modality Therapy; Complex; DSP 4; Dementia; Development; Disease; Dopamine; Drug usage; Equilibrium; General Population; Genes; Genetic Recombination; Goals; Healthcare; Human; Impulse Control Disorders; Knockout Mice; Laboratories; Lesion; Levodopa; Life Expectancy; Light; Link; LoxP-flanked allele; Mediating; Mental Depression; Minor; Mission; Modeling; Molecular; Monitor; Mood Disorders; Morbidity - disease rate; Motor; Movement; Movement Disorders; Mus; Neurodegenerative Disorders; Neurologic; Neurons; Neurotoxins; Norepinephrine; Parkinson Disease; Patient Self-Report; Patients; Pharmacological Treatment; Population; Process; Quality of life; Research; Role; Sensory; Serotonin; Sleep; Sleep Disorders; Synapses; System; TPH2; Tamoxifen; Targeted Toxins; Testing; Therapeutic Effect; Time; Treatment Efficacy; Tremor; Veterans; Work; abstracting; aged; cognitive testing; disability; dopaminergic neuron; effective therapy; equilibration disorder; health related quality of life; innovation; interest; monoamine; mortality; motor deficit; motor symptom; mouse model; neurochemistry; neuron loss; neuropsychiatry; non-motor symptom; noradrenaline transporter; novel; novel therapeutic intervention; offspring; psychological distress; receptor; research study; restoration; symptomatology; translational approach; treatment effect

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.

项目总结/摘要 帕金森病（PD）是仅次于阿尔茨海默病的第二种最常见的神经退行性疾病， 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）神经元系统，引起众所周知的震颤运动缺陷， 运动迟缓、僵硬和姿势不稳定。PD的一线药物治疗是左旋多巴， 其目的是补充大脑DA水平，从而从这些运动中提供显著缓解 问题它尚未得到广泛重视，但血清素（5 HT）和去甲肾上腺素（NE）神经元系统受到广泛重视 在PD中也严重退化。虽然如此多的注意力集中在电机上是合适的， 帕金森病的诊断学，增加对帕金森病非运动表现的兴趣是根据事实需要的 大约80%的PD患者患有共病神经精神疾病，如睡眠 精神障碍、焦虑和痴呆。最普遍的情感障碍是抑郁症。非运动症状 (NMS)无论是与疾病过程相关还是由L-DOPA诱导，PD的发生都不是微不足道的， 残疾恶化、生活质量受损和预期寿命缩短。事实上，已经确定， 帕金森病的NMS对健康相关生活质量的影响大于运动症状。并明确 PD中的情感障碍不仅仅是由于发展而引起的心理困扰的结果， 慢性衰弱性疾病PD的许多NMS可以合理地联系到功能的减少， 5 HT和NE神经元系统，这是加强了通常遵循的策略时，治疗NMS的 PD-使用增加这些单胺的突触水平或激活其受体的药物。这些 治疗（即5 HT和NE转运蛋白的阻断剂，受体激动剂）还没有那么有效， 有的甚至反对左旋多巴的治疗效果。本申请研究的基本原理 首先认识到，在DA神经元大量丢失的情况下，5 HT和NE的缺陷可能 有助于PD的NMS。NMS的出现不能用DA的单一丢失来解释 神经元PD本申请中的拟议工作将利用我们实验室的可用性， 缺乏色氨酸羟化酶2（TPH 2）基因的创新小鼠模型。这种新模式是 使用Cre-ERT 2-Lox重组方法诱导他莫昔芬后TPH 2和5 HT的丢失 成年小鼠的治疗。将用1-甲基-4-苯基-1，2，3，6-四氢呋喃（1-methyl-4-phenyl-1，2，3，6-dichloroethane）处理具有5 HT缺陷的小鼠。 四氢吡啶（MPTP），一种靶向多巴胺神经元进行破坏的神经毒素，和/或与N-（2- 氯乙基）-N-乙基-2-溴苄胺（DSP-4），一种靶向NE神经元的高度选择性毒素。的 NMS的出现将使用一组行为，神经，神经化学和认知 试验.此后，缺乏单胺的小鼠将用L-DOPA、L-DOPS（屈昔多巴）和/或5-羟丙甲酰胺（Droxidopa）处理。 HTP分别补充脑内DA、NE和5 HT水平。假设帕金森病的NMS出现， 当DA神经元在5 HT和NE耗竭的背景下丢失时。进一步假设5-HTP和 L-DOPS可有效缓解PD的NMS，而不降低L-DOPA的治疗效果。 治疗运动缺陷5-HTP和L-DOPS分别是5 HT和NE的氨基酸前体， 已经在许多临床试验中用于治疗人类。因此，它们的使用，以减少NMS的PD 代表了一种安全、简单和可转化的方法。