Ghrelin Agonists Multiple Beneficial Effects on Parkinson's Non-Motor Symptoms

生长素释放肽激动剂对帕金森氏症非运动症状有多种有益作用

• 批准号: 10174739
• 负责人: LIXIN WANG
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174739
• 关键词: Abdomen; Agonist; Animal Model; Anorexia Nervosa; Anti-Inflammatory Agents; Appetite Stimulants; Behavior monitoring; Blood Circulation; Body Composition; Body Weight; Body Weight Changes; Body Weight decreased; Body fat; Brain; Cachexia; Chronic; Clinical; Clinical Research; Colon; Complex; Constipation; Data; Defecation; Degenerative Disorder; Development; Disease; Disease model; Distal; Drug Kinetics; Eating; Energy Intake; Energy Metabolism; Enteral; Equipment; Experimental Designs; Functional disorder; Gastric Emptying; Gastrointestinal tract structure; Gastroparesis; Genetic Models; Grant; Hormones; Human; Hydroxydopamines; Inflammation; Intestinal permeability; Levodopa; Life; Magnetic Resonance Imaging; Manometry; Measures; Metabolic; Metabolism; Microinjections; Modeling; Monitor; Motor; Movement; Mucous Membrane; Mus; Nature; Nerve; Nerve Degeneration; Neurons; Neurotoxins; Oral; Oral Administration; Output; Parkinson Disease; Pathologic; Patients; Pattern; Peripheral; Permeability; Phase; Pressure Transducers; Quality of life; Rattus; Reporting; Research; Rodent; Rodent Model; Severities; Signal Transduction; Stress; Symptoms; System; Testing; Veterans; Water; Water consumption; Weight; Weight Gain; Work; adipsia; alpha synuclein; behavior test; blood-brain barrier crossing; cell motility; dopaminergic neuron; feeding; ghrelin; ghrelin receptor; imaging system; improved; increased appetite; median forebrain bundle; miniaturize; motor deficit; motor disorder; motor impairment; motor symptom; mouse model; neuroinflammation; neuroprotection; neurotransmission; nigrostriatal system; non-motor symptom; novel; novel strategies; overexpression; pre-clinical; pressure; prevent; promoter; public health relevance; screening; solid state

 DESCRIPTION: PD has a complex of motor and non-motor symptoms with progressive dopaminergic (DA) and non-DA neurodegeneration in multisystem. There is paucity in treatment for non-motor symptoms that include delayed gastric emptying and more prominently constipation, weight loss and reduced water intake. The underlying mechanisms are largely unknown and involve both central and peripheral alterations. Inflammation was found in the brains of PD patients, as well as animal models of PD, which may promote degeneration of DA neurons, is correlated to motor symptom severity and might contribute to the development of non-motor symptoms. An animal model for PD induced by a neurotoxin, 6-hydroxydopamine (6-OHDA) microinjected unilaterally in the medial forebrain bundle of rats, has partial loss of DA neurons. Beside motor disorders, the rats have constipation, and reduced water intake and body weight as in PD patients. We also previously reported constipation-like disorders and less weight gain in a genetic model (Thy1-asyn mice). Ghrelin is a gut hormone and it has orexigenic and prokinetic effect on the gut through peripheral and central mechanisms. PD patients with body weight loss have lower basal circulating levels of ghrelin, and do not show the late phase postprandial rise suggesting dampened ghrelin release and/or synthesis. Our preliminary data showed that systemic administration of a ghrelin agonist, anamorelin increased body weight and food intake in Thy1-aSyn mice. However, systemic ghrelin did not stimulate the colonic motility, while ghrelin agonist crossing the blood- brain barrier (BBB) did. We showed that a BBB-crossing ghrelin agonist, HM01 increased defecation in 6- OHDA rats. More importantly, ghrelin has anti-inflammatory and neuroprotective effect on DA neurons. Ghrelin agonists have advantages over ghrelin as they are orally active and long acting. The hypothesis is that ghrelin agonists have multiple beneficial effects on PD symptoms via gut prokinetic, orexigenic, dipsogenic and anabolic actions that involve distinct mechanisms. We will validate the ghrelin agonist effects in two animal models which display different PD pathological features, because no animal model recapitulates the progressive nature and complexity of human PD. The effects of BBB crossing (HM01) and non-BBB crossing (anamorelin) agonists will be compared and the targets will be assessed. (1) To assess ghrelin agonists' effect on constipation and altered colonic signals in 6-OHDA rats and Thy1-asyn mice. After oral administration of HM01 or anamorelin, fecal output and water content will be monitored, colonic motility will be measured using a non-invasive miniaturized pressure transducer. The permeability of the distal ileal and colonic mucosa will be assessed in Ussing's chambers. (2) To assess whether ghrelin agonists reduce loss of body weight and fat mass and improve feeding and water intake. HM01 and anamorelin effect in Thy1-asyn and wide type mice on food and water intake, body weight will be monitored simultaneously with energy intake and expenditure using a state-of-art automated metabolism screening system, and meal pattern by an automated feeding episode monitoring system. Ghrelin agonists' effect on body composition of Thy1-aSyn mice and 6-OHDA rats will be measured in rodent MRI equipment, as well as on water intake in 6-OHDA rats. (3) To assess ghrelin agonist effect on PD symptoms in 6-OHDA rats under L-dopa treatment, such as constipation, body weight loss, motor dysfunctions and L-dopa-induced delayed gastric emptying. The related signals in the colon and brain will be measured after ghrelin agonist and L-dopa treatment. This study will help to further validate ghrelin agonists' effect on neuroinflammation and neuroprotection in the nigrostriatal system in the animal models. Treating non- motor symptoms is one of the priorities in PD research. This project will provide preclinical evidence for novel beneficial effects of ghrelin agonists to alleviate constipation, adipsia and weight loss, as well as motor deficits in PD including Veterans who are more vulnerable under stress.

 描述： PD具有多巴胺能（DA）的运动和非运动症状的复合体和多种神经退行性的复合体。非运动症状的治疗缺乏，包括延迟的胃排空和更突出的便秘，体重减轻和摄入量减少。基本机制在很大程度上是未知的，并且涉及中央和周围变化。在PD患者的大脑以及PD的动物模型中发现了炎症，可能促进DA神经元的变性，与运动症状的严重程度相关，并可能有助于非运动症状的发展。由神经毒素，6-羟基多巴胺（6-OHDA）诱导的PD动物模型，在大鼠内侧前脑束中单侧单侧显微注射，具有DA神经元的部分损失。除运动障碍外，大鼠具有便秘，并且像PD患者一样减少了水的摄入量和体重。我们先前还报道了遗传模型（THY1-ASYNC小鼠）中的便秘疾病，体重增加较小。生长素素是一种肠道，它通过外围和中央机制对肠道具有甲状腺素和原始作用。体重减轻的PD患者的生长素蛋白的碱性循环水平较低，并且没有显示餐后上升的升高表明该死的生长素释放蛋白释放和/或合成。我们的初步数据表明，thy1-assyn小鼠中的血肠蛋白激动剂的全身性给药增加了体重和食物摄入量。然而，全身性生长素没有刺激结肠运动性，而越过血脑屏障（BBB）的ghrelin激动剂也没有刺激结肠运动。我们表明，BBB横断的发肠肽激动剂，HM01增加了6- ohda大鼠的排便。更重要的是，生长素素对DA神经元具有抗炎和神经保护作用。 Ghrelin激动剂比Ghrelin具有优势，因为它们是口服活跃且长期表现的。假设是，生长素素激动剂对PD症状具有多种有益作用，该肠道脑，甲状腺素，倾向，倾基和合成代谢作用涉及不同的机制。我们将在两种显示出不同的PD病理特征的动物模型中验证肽释放蛋白激动剂的作用，因为没有动物模型概述了人类PD的渐进性和复杂性。将比较BBB交叉（HM01）和非BBB交叉（Anamorelin）激动剂的影响，并将评估目标。 （1）评估6-OHDA大鼠和Thy1-Async小鼠中的胡格勒蛋白激动剂对便秘的影响并改变了结肠信号。在口服HM01或Anamorelin的口服后，将监测粪便和水含量，将使用非侵入性微型化压力换能器测量结肠运动。卵形和结肠粘膜远端的渗透性将在Ussing的室中进行评估。 （2）评估生长素素激动剂是否减少体重和脂肪质量的损失，并改善进食和摄入量。 HM01和Anamorelin效果在Thy1-酶和宽类型小鼠中对食物和水的摄入量，体重将通过能量摄入和支出来监测体重，并使用自动喂养疗法监测系统使用最先进的自动代谢筛查系统，而用餐模式。在啮齿动物的MRI设备以及6-OHDA大鼠的水摄入量中，将测量生长素素激动剂对Thy1-Asyn小鼠和6-OHDA大鼠的身体组成的影响。 （3）在L-DOPA治疗下，评估6-OHDA大鼠的PD症状的影响，例如便秘，体重减轻，运动功能障碍和L-DOPA诱导的延迟胃排空。结肠和大脑中的相关信号这项研究将有助于进一步验证血肠肽激动剂对动物模型中黑质纹状体系统中神经炎症和神经保护作用的影响。治疗非运动症状是PD研究的优先事项之一。该项目将提供临床前证据，以减轻临床前的有益作用，以减轻便秘，adipsia和体重减轻，运动在PD中定义了包括在压力下更容易受到脆弱的退伍军人。