Background:Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. Objective:Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. Methods:GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results:Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion:These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.

中文翻译：

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角鲨胺在帕金森病小鼠模型中恢复肠神经系统的功能。

背景：帕金森病 (PD) 是一种进行性神经退行性疾病，被认为是由大脑、自主神经和肠神经系统 (ENS) 内 α-突触核蛋白 (α-syn) 的积累引起的。ENS 在 PD 中的参与通常在 PD 的经典运动症状出现之前很多年，当时严重便秘代表了主要的发病率。在体外和体内进行的研究表明，角鲨胺是一种两性离子两亲性氨基甾醇，最初从角鲨的肝脏中分离出来，可以有效地取代膜结合的 α-syn。目的：在这里，我们探讨了角鲨胺对 PD 小鼠模型胃肠 (GI) 道的电生理作用，该模型被设计为表达高度​​聚集的 A53T 人 α-syn 突变体。方法：使用体外组织运动方案和通过粪便颗粒输出评估 PD 模型小鼠和对照对口服角鲨胺的 GI 运动和体内反应。使用来自空肠的细胞外肠系膜神经记录测量对角鲨胺的迷走神经传入反应。进行全细胞膜片钳以测量肌间神经丛中对角鲨胺的反应。结果：角鲨胺在体内和局部应用于肠道的几分钟内有效地恢复了紊乱的结肠运动。我们表明，局部接触 ENS 的内在初级传入神经元 (IPAN) 的角鲨胺可迅速恢复兴奋性。结论：这些观察结果可能有助于解释角鲨胺如何通过对 ENS 中 IPAN 的局部影响来促进肠道推进活动，