帕金森病早期非运动症状胃肠道功能障碍的中枢机制及早期干预研究

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons originating in the substantia nigra. Braak hypothesized that alpha-synuclein spreads through the brain in a predictable ascending manner and proposed a 6-step pathological staging system for PD. This early pathological change in the enteric nervous system (ENS) and dorsal motor nucleus (DMV) is pertinent to consideration of the pathophysiology of delayed gastric emptying in early PD. Gastrointestinal dysfunction is common in all stages of PD, accounting for 98.6% PD patients. However, the central mechanisms underlying the gastrointestinal dysfunction in PD remain largely unknown. Our previous studies show decreased plasma ghrelin levels in the early stage of PD patients, which might partially accounts for the gastrointestinal dysfunction. To further illustrate the underlying mechanism, in the present study, we detected the changes of the gastrointestinal motility in different stages of PD. Meanwhile, the plasma ghrelin levels and function of ENS and DMV neurons are also determined. The changes of motor activity and degeneration of nigral dopaminergic neurons are also observed. The changes of the gastrointestinal motility and motor activity are detected, as well as the neuronal function of ENS, DMV and subtantia nigra. Two kinds of PD animal models are used in this study, one is PD transgenic mice expressing the prion promoter driven human A53T mutation, the other is chronic PD models by employing an intragastrical rotenone intoxication. Since ghrelin is a hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD, intravenous injection of ghrelin is applied to the two PD models in the very early stage. The results are further strengthened in PD transgenic mice with ghrelin receptor GHSR knockdown. This study could supply some evidence that dysfunctions of ENS and DMV neurons in early PD stages result in impaired release of ghrelin, which might account of the disturbed gastrointestinal motility. Early application of ghrelin might improve the symptoms and delay the progression of PD.

帕金森病（PD）已不再是黑质变性所致的区域性神经疾病，而是累及中枢和外周的全身性疾病，在出现运动症状前，98.6%的患者会出现一些非运动症状，以胃肠道功能障碍发生率最高。然而，PD胃肠道功能障碍的中枢机制尚不清楚。在前期工作中，我们观察到PD早期Ghrelin含量降低，可能是导致胃肠道功能障碍的原因之一，为了探讨其机制，拟在携带人突变型alpha-突触核蛋白的PD转基因小鼠和慢性鱼藤酮灌胃小鼠PD模型上，观察疾病不同时期胃肠道功能变化与Ghrelin含量、ENS和DMV神经元功能之间的关系，及其与黑质多巴胺能神经元功能改变之间的关系，进一步在Ghrelin受体敲除的PD转基因小鼠上验证，并评价Ghrelin的早期干预效果。本研究将证实PD早期胃肠道功能障碍的出现是由于ENS和DMV神经元功能障碍，导致Ghrelin含量降低所致，早期应用Ghrelin干预能够改善症状并延缓疾病进程。

胃肠道功能障碍是帕金森病（Parkinson’s disease,PD）的一种常见的非运动症状，其中枢机制尚不清楚。Ghrelin是支配胃肠道运动的激素之一，其分泌的中枢调控在脑干的迷走神经背侧运动核（DMV）。本研究发现PD病人血浆ghrelin水平降低，其水平不随临床分期而改变。同时在PD转基因小鼠上，观察疾病不同时期胃肠道功能变化与血浆ghrelin含量之间的关系，并阐明其变化是DMV神经元功能障碍所致。Ghrelin可能作为PD中反映中枢DMV病变的一个血浆标记物，在PD的运动症状出现前，间接反映脑内核团的早期病变。而早期应用ghrelin进行干预，能够纠正血浆中ghrelin水平的降低，使其维持在正常水平，延缓黑质多巴胺能神经元的死亡过程，从而起到早期预防干预PD的研究目的。本研究将为血浆中ghrelin含量的变化作为PD早期诊断的生物标记物提供实验依据，为ghrelin作为神经保护药物的开发提供理论基础，结合PET影像学诊断，将有助于PD的早期诊断，具有重要的临床应用价值。