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 具有复杂的运动和非运动症状，伴有多系统进行性多巴胺能 (DA) 和非 DA 神经变性。非运动症状的治疗方法很少，包括胃排空延迟以及更明显的便秘、体重减轻和饮水量减少。其潜在机制在很大程度上尚不清楚，并且在 PD 患者以及 PD 动物模型中发现了涉及中枢和外周改变的炎症，这可能会促进 DA 神经元的变性。与运动症状严重程度相关，并可能导致非运动症状的发生。在大鼠内侧前脑束单侧注射神经毒素 6-羟基多巴胺 (6-OHDA) 诱导的 PD 动物模型中，DA 部分丧失。除了运动障碍外，大鼠还出现便秘、饮水量减少和体重下降，与帕金森病患者一样，我们之前在遗传模型中也报道过类似便秘的疾病和体重增加较少。 （Thy1-asyn 小鼠）。Ghrelin 是一种肠道激素，通过外周和中枢机制对肠道产生促食欲和促动力作用。体重减轻的 PD 患者的基础循环 Ghrelin 水平较低，且餐后后期不表现出生长素释放肽。我们的初步数据表明，全身施用生长素释放肽激动剂阿拉莫林会增加 Thy1-aSyn 小鼠的体重和食物摄入量。然而，全身性生长素释放肽不会刺激结肠运动，而跨越血脑屏障（BBB）的生长素释放肽激动剂则会刺激结肠运动。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，因为它们具有口服活性且长效。胃饥饿素激动剂通过涉及不同机制的肠道促运动、食欲促进、促进和合成代谢作用对帕金森病症状具有多种有益作用，我们将在表现出不同帕金森病病理特征的两种动物模型中验证胃饥饿素激动剂的作用，因为没有动物模型能够概括这些作用。将比较 BBB 交叉 (HM01) 和非 BBB 交叉（阿拉莫林）激动剂的作用并评估目标 (1)。为了评估 ghrelin 激动剂对 6-OHDA 大鼠和 Thy1-asyn 小鼠的便秘和结肠信号改变的影响，口服 HM01 或阿拉莫林后，将监测粪便排出量和水含量，并使用非侵入性测量结肠运动。微型压力传感器。远端回肠和结肠粘膜的渗透性将在尤斯室中进行评估（2）以评估是否。生长素释放肽激动剂可减少体重和脂肪量的损失，并改善 Thy1-asyn 和宽型小鼠的摄食和水摄入量，将使用状态监测仪同时监测体重和能量摄入和消耗。最先进的自动代谢筛选系统，以及自动喂养事件监测系统的膳食模式将在啮齿类动物中测量 Thy1-aSyn 小鼠和 6-OHDA 大鼠身体成分的影响。 MRI 设备以及对 6-OHDA 大鼠饮水量的影响 (3) 评估 ghrelin 激动剂对左旋多巴治疗下的 6-OHDA 大鼠 PD 症状（如便秘、体重减轻、运动功能障碍和 L-）的影响。多巴引起的胃排空延迟将在胃饥饿素激动剂和左旋多巴治疗后测量结肠和大脑中的相关信号，本研究将有助于进一步验证胃饥饿素激动剂对胃排空的影响。治疗动物模型黑质纹状体系统的神经炎症和神经保护是 PD 研究的重点之一，该项目将为 ghrelin 激动剂缓解便秘、口渴和体重减轻的新有益作用提供临床前证据。帕金森病中的运动缺陷，包括在压力下更容易受到伤害的退伍军人。