Minalyan Artem, Gabrielyan Lilit, Pietra Claudio, Taché Yvette, Wang Lixin
Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States.
Helsinn SA Lugano, Lugano, Switzerland.
Front Integr Neurosci. 2019 Apr 12;13:13. doi: 10.3389/fnint.2019.00013. eCollection 2019.
: Developing therapy for non-motor symptoms of Parkinson's disease (PD) is important for improving patients' quality of life. Previously, we reported that the ghrelin receptor agonist, HM01 normalized the decreased 4-h fecal output and levodopa-inhibited gastric emptying in 6-OHDA rats, and activated selective areas in brain and spinal cord. In this study, we evaluated whether chronic HM01 treatment influences motor functions and/or has beneficial effects on non-motor symptoms including alterations of body weight and composition, defecation, feeding and water intake in 6-OHDA rats. : Male rats were microinjected unilaterally into the medial forebrain bundle with either vehicle or 6-OHDA. Three weeks later, we assessed basal body weight, and 24-h fecal output (pellets, weight, dry weight and water content), water intake and food intake (ingested and spillage). Then, HM01 (3 mg/kg) or vehicle was given per gavage daily for 10-12 days and the same parameters were re-assessed daily. Motor behavior (stepping and rotations tests), body composition were monitored before and after the HM01 treatment. : 6-OHDA rats showed motor deficits in rotation test induced by apomorphine and stepping test. They also displayed a significant reduction in body weight, water consumption, fecal weight and water content and an increase in food spillage compared to vehicle microinjected rats. Daily oral treatment of HM01 did not modify motor alterations compared to vehicle but significantly increased the body weight, fat mass, and 24-h fecal weight, fecal water content, food and water intake in 6-OHDA rats, while HM01 had no significant effect in vehicle microinjected rats. Fecal weight and water content were both correlated with water intake, but not with food intake. Fat mass, but not body weight, was correlated with food intake. HM01 effects were significant after 24 h and remained similar during the treatment. : Chronic treatment with ghrelin agonist, HM01 improved several non-motor symptoms in the rat PD model induced by 6-OHDA lesion including the decrease in body weight, water consumption, fecal weight and water content, and increased food intake while not improving the motor deficits. These findings provide pre-clinical evidence of potential benefits of ghrelin agonists to alleviate non-motor symptoms in PD patients.
开发针对帕金森病（PD）非运动症状的治疗方法对于改善患者生活质量至关重要。此前，我们报道胃饥饿素受体激动剂HM01可使6-羟基多巴胺（6-OHDA）大鼠减少的4小时粪便排出量和左旋多巴抑制的胃排空恢复正常，并激活脑和脊髓中的特定区域。在本研究中，我们评估了长期给予HM01治疗是否会影响运动功能和/或对6-OHDA大鼠的非运动症状产生有益影响，这些非运动症状包括体重和身体组成的改变、排便、进食和饮水情况。：雄性大鼠单侧脑室内微量注射溶剂或6-OHDA。三周后，我们评估基础体重、24小时粪便排出量（粪便粒数、重量、干重和含水量）、饮水量和食物摄入量（摄入和溢出量）。然后，每天经口灌胃给予HM01（3mg/kg）或溶剂，持续10 - 12天，并每天重新评估相同参数。在给予HM01治疗前后监测运动行为（踏步和旋转试验）、身体组成。：6-OHDA大鼠在阿扑吗啡诱导的旋转试验和踏步试验中表现出运动缺陷。与注射溶剂的大鼠相比，它们的体重、饮水量、粪便重量和含水量也显著降低，食物溢出量增加。与溶剂相比，每天口服HM01并未改变运动改变，但显著增加了6-OHDA大鼠的体重、脂肪量、24小时粪便重量、粪便含水量、食物和饮水量，而HM01对注射溶剂的大鼠无显著影响。粪便重量和含水量均与饮水量相关，但与食物摄入量无关。脂肪量而非体重与食物摄入量相关。HM01的作用在24小时后显著，并在治疗期间保持相似。：长期给予胃饥饿素激动剂HM01可改善6-OHDA损伤诱导的大鼠PD模型中的几种非运动症状，包括体重、饮水量、粪便重量和含水量的减少以及食物摄入量的增加，而未改善运动缺陷。这些发现为胃饥饿素激动剂缓解PD患者非运动症状潜在益处提供了临床前证据。
