Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson’s disease (PD). We tested the hypothesis that gastric co-administration of subthreshold doses of lectins and paraquat can recreate the pathology and behavioral manifestations of PD in rats. A solution containing paraquat + lectin was administered daily for 7 days via gastric gavage, followed by testing for Parkinsonian behavior and gastric dysmotility. At the end of the experiment, brainstem and midbrain tissues were analyzed for the presence of misfolded α-synuclein and neuronal loss in the SNpc and in the dorsal motor nucleus of the vagus (DMV). Misfolded α-synuclein was found in DMV and SNpc neurons. A significant decrease in tyrosine hydroxylase positive dopaminergic neurons was noted in the SNpc, conversely there was no apparent loss of cholinergic neurons of the DMV. Nigrovagally-evoked gastric motility was impaired in treated rats prior to the onset of parkinsonism, the motor deficits of which were improved by l-dopa treatment. Vagotomy prevented the development of parkinsonian symptoms and constrained the appearance of misfolded α-synuclein to myenteric neurons. These data demonstrate that co-administration of subthreshold doses of paraquat and lectin induces progressive, l-dopa-responsive parkinsonism that is preceded by gastric dysmotility. This novel preclinical model of environmentally triggered PD provides functional support for Braak’s staging hypothesis of idiopathic PD.

越来越多的证据表明，环境神经毒物或由此类神经毒物产生的错误折叠的 α-突触核蛋白通过迷走神经从胃肠道转运到中枢神经系统，引发黑质致密部 (SNpc) 多巴胺能神经元的变性，并导致帕金森病。 PD）。我们测试了这样的假设：在胃中同时给予阈下剂量的凝集素和百草枯可以在大鼠中重现帕金森病的病理和行为表现。每天通过胃管饲法施用含有百草枯+凝集素的溶液，持续 7 天，然后测试帕金森行为和胃动力障碍。实验结束时，分析脑干和中脑组织中是否存在错误折叠的 α-突触核蛋白以及 SNpc 和迷走神经背运动核 (DMV) 中的神经元丢失。在 DMV 和 SNpc 神经元中发现了错误折叠的 α-突触核蛋白。 SNpc 中酪氨酸羟化酶阳性多巴胺能神经元显着减少，相反，DMV 胆碱能神经元没有明显损失。在帕金森病发作之前，接受治疗的大鼠中黑迷走神经诱发的胃动力受损，其运动缺陷通过左旋多巴治疗得到改善。迷走神经切断术阻止了帕金森病症状的发展，并限制了错误折叠的 α-突触核蛋白在肌间神经元中的出现。这些数据表明，共同施用阈下剂量的百草枯和凝集素会诱发进行性左旋多巴反应性帕金森病，随后出现胃动力障碍。这种环境引发的帕金森病的新型临床前模型为 Braak 的特发性帕金森病分期假说提供了功能支持。