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: 8867918
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867918
• 关键词: Abdomen; Agonist; Animal Model; Anorexia Nervosa; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Blood - brain barrier anatomy; Blood Circulation; Body Composition; Body Weight; Body Weight Changes; Body Weight decreased; Body fat; Brain; 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; Inflammation; Levodopa; Life; Magnetic Resonance Imaging; Manometry; Measures; Metabolic; Metabolism; Microinjections; Modeling; Monitor; Motor; Movement; Mucous Membrane; Mus; Nature; Nerve; Nerve Degeneration; Neurons; Neurotoxins; Oral Administration; Output; Oxidopamine; Parkinson Disease; 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; cell motility; dopaminergic neuron; feeding; ghrelin; ghrelin receptor; imaging system; improved; increased appetite; median forebrain bundle; miniaturize; motor deficit; motor disorder; motor impairment; 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.

 产品说明： PD是一种复杂的运动和非运动症状，伴有多系统进行性多巴胺能和非多巴胺能神经元变性。对非运动症状的治疗很少，包括胃排空延迟和更突出的便秘、体重减轻和饮水量减少。潜在的机制在很大程度上是未知的，涉及中央和外周的变化。在PD患者的脑中发现了炎症，以及PD的动物模型，其可能促进DA神经元的变性，与运动症状严重程度相关，并且可能有助于非运动症状的发展。在大鼠内侧前脑束单侧微量注射神经毒素6-羟基多巴胺（6-OHDA）诱导的PD动物模型中，DA神经元部分丢失。除了运动障碍外，大鼠还具有便秘，以及与PD患者相同的水摄入量和体重减少。我们以前也报道过便秘样疾病和遗传模型（Thy 1-asyn小鼠）中体重增加较少。Ghrelin是一种肠道激素，通过外周和中枢机制对肠道具有促食欲和促动力作用。具有体重减轻的PD患者具有较低的胃饥饿素的基础循环水平，并且没有显示出晚期餐后升高，这表明胃饥饿素的释放和/或合成受到抑制。我们的初步数据显示，全身给予生长激素释放肽激动剂阿拉莫林增加了Thy 1-aSyn小鼠的体重和食物摄入量。然而，系统性ghrelin并不刺激结肠运动，而ghrelin激动剂穿过血脑屏障（BBB）则刺激结肠运动。我们发现，一种BBB交叉生长激素释放肽激动剂，HM 01增加了6- OHDA大鼠的排便。更重要的是，ghrelin对DA神经元具有抗炎和神经保护作用。生长素释放肽激动剂具有优于生长素释放肽的优点，因为它们是口服活性和长效的。该假说是生长素释放肽激动剂通过涉及不同机制的肠道促动力、食欲、致渴和合成代谢作用对PD症状具有多种有益作用。我们将在两种显示不同PD病理特征的动物模型中验证ghrelin激动剂的作用，因为没有动物模型能概括人类PD的进行性和复杂性。将比较BBB穿越（HM 01）和非BBB穿越（阿拉莫林）激动剂的作用，并将评估靶点。(1)评估ghrelin激动剂对6-OHDA大鼠和Thy 1-asyn小鼠便秘和结肠信号改变的影响。口服HM 01或阿拉莫林后，将监测粪便排出量和含水量，并使用无创小型压力传感器测量结肠蠕动。将在Ussing室中评估远端回肠和结肠粘膜的渗透性。(2)评估生长激素释放肽激动剂是否能减少体重和脂肪量的减少，并改善摄食量和饮水量。HM 01和阿拉莫林在Thy 1-asyn和野生型小鼠中对食物和水摄入量的影响，将使用最先进的自动代谢筛选系统同时监测体重和能量摄入和消耗，并通过自动喂养事件监测系统监测进餐模式。将在啮齿动物MRI设备中测量Ghrelin激动剂对Thy 1-aSyn小鼠和6-OHDA大鼠的身体组成的影响，以及对6-OHDA大鼠的饮水量的影响。(3)评估Ghrelin激动剂对L-多巴治疗的6-OHDA大鼠的PD症状的作用，如便秘、体重减轻、运动功能障碍和L-多巴诱导的胃排空延迟。将在ghrelin激动剂和L-多巴处理后测量结肠和脑中的相关信号。本研究将有助于进一步验证ghrelin激动剂在动物模型中对黑质纹状体系统神经炎症和神经保护的作用。非运动症状的治疗是帕金森病研究的重点之一.该项目将提供临床前证据，证明生长激素释放肽激动剂在缓解便秘、厌食和体重减轻以及PD运动缺陷（包括在压力下更脆弱的退伍军人）方面的新型有益作用。