Data_Sheet_2_Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease.PDF

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.

帕金森病（Parkinson's disease, PD）已被证实可累及外周神经系统（peripheral nervous system, PNS）与肠神经系统（enteric nervous system, ENS）。外周神经系统与肠神经系统的功能改变早在疾病病程早期即已出现，并与PD患者的诸多非运动症状相关——例如便秘（constipation），这类症状可早于运动症状（motor symptoms）数年出现。本研究针对杀虫剂鱼藤酮（rotenone，一种线粒体复合物I抑制剂（mitochondrial Complex I inhibitor））展开探究，通过组织浴槽法检测肠道收缩功能（intestinal contractility），并分析相关蛋白质表达（protein expression），以明确其对肠神经系统功能与神经元组成的影响。结果显示，鱼藤酮可改变肠道对卡巴胆碱（carbachol）、多巴胺（dopamine）及电场刺激（electric field stimulation, EFS）的正常生理应答。对电场刺激的应答改变似乎与胆碱能输入（cholinergic input）减少相关，同时也与去甲肾上腺素能输入（noradrenergic input）有关，这一结论可由鱼藤酮暴露小鼠在电场刺激下的非肾上腺素能非胆碱能（non-adrenergic non-cholinergic, NANC）应答得到佐证。这类改变的程度与方向因肠道区域及暴露时长而异，且与鱼藤酮暴露小鼠体内多巴胺能、胆碱能及肾上腺素能受体（adrenergic receptors）的早期上调（up-regulation），以及肠神经元（enteric neurons）数量的不规则减少密切相关。在该小鼠模型（mouse model）中，这类改变早在黑质（substantia nigra）受累前即已出现，提示此类改变也可在PD患者运动症状发作前被观测到，因此它们有望成为早期检测帕金森病的理想影像学标志物（radiological markers）候选对象。