Chronic rotenone exposure reproduces Parkinson's disease gastrointestinal neuropathology
Chronic rotenone exposure reproduces Parkinson's disease gastrointestinal neuropathology
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DOI：
10.1016/j.nbd.2009.06.017
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发表时间：
2009-10-01
影响因子：
6.1
通讯作者：
Greenamyre, J. Timothy
中科院分区：
文献类型：
--
作者：
Drolet, Robert E.;Cannon, Jason R.;Greenamyre, J. Timothy
胃肠道疾病，特别是严重便秘和胃排空延迟，是影响大多数患者的帕金森病的核心症状。然而，这种功能障碍的神经病理学基础和生理学基础尚不清楚。为了开始在 PD 实验室模型中探索这些现象，用媒介物或鱼藤酮（2.0 mg/kg，腹腔注射；5 天/周）治疗大鼠 6 周。最后一次鱼藤酮注射后 3 天和 6 个月评估肌间神经丛 α-突触核蛋白聚合病理学和神经元损失。最后一次鱼藤酮注射后 3 天、1 个月和 6 个月评估胃肠动力。鱼藤酮治疗导致 α-突触核蛋白免疫反应性急剧降低，但 6 个月后，聚集病理学和细胞质内含物显着增加，其外观与特发性 PD 中的肠道路易体相似。鱼藤酮治疗的大鼠在治疗 6 个月后，小肠肌间神经元也出现中度但永久性的损失，并且胃肠道蠕动适度减慢。我们的结果表明，有限地接触环境毒物可能会导致肠神经系统中帕金森病α-突触核蛋白病理的延迟出现以及胃肠道运动的相关功能缺陷。因此，鱼藤酮模型可能提供一种研究帕金森病胃肠道功能障碍的致病机制和测试新的治疗干预措施的方法。 (C) 2009 Elsevier Inc. 保留所有权利。
Gastrointestinal disorders, particularly severe constipation and delayed gastric emptying, are core symptoms of Parkinson's disease that affect most patients. However, the neuropathological substrate and physiological basis for this dysfunction are poorly defined. To begin to explore these phenomena in laboratory models of PD, rats were treated with either vehicle or rotenone (2.0 mg/kg, i.p.; 5 days/week) for 6-weeks. Myenteric plexus alpha-synuclein aggregate pathology and neuron loss were assessed 3-days and 6-months after the last rotenone injection. Gastrointestinal motility was assessed at 3-days, 1-month and 6-months after the last rotenone injection. Rotenone treatment caused an acute reduction in alpha-synuclein-immunoreactivity, but this was followed 6 months later by a robust increase in aggregate pathology and cytoplasmic inclusions that were similar in appearance to enteric Lewy-bodies in idiopathic PD. Rotenone-treated rats also had a moderate but permanent loss of small intestine myenteric neurons and an associated modest slowing of gastrointestinal motility 6-months after treatment. Our results suggest that a circumscribed exposure to an environmental toxicant can cause the delayed appearance of parkinsonian alpha-synuclein pathology in the enteric nervous system and an associated functional deficit in gastrointestinal motility. The rotenone model may therefore, provide a means to investigate pathogenic mechanisms and to test new therapeutic interventions into gastrointestinal dysfunction in PD. (C) 2009 Elsevier Inc. All rights reserved.