Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice.
Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice.
复制标题
DOI：
10.1371/journal.pone.0008762
复制
发表时间：
2010-01-19
期刊：
影响因子：
3.7
通讯作者：
Funk RH
中科院分区：
文献类型：
--
作者：
Pan-Montojo F;Anichtchik O;Dening Y;Knels L;Pursche S;Jung R;Jackson S;Gille G;Spillantini MG;Reichmann H;Funk RH
在帕金森病（PD）患者中，相关病理遵循一个特征性模式，除其他外，包括肠神经系统（ENS）、迷走神经背运动核（DMV）、脊髓中外侧核和黑质，这为疾病的神经病理分期提供了基础。在这里，我们报告了在患者中发现，胃内施用鱼藤酮（一种常用的抑制线粒体呼吸链复合体I的农药）能够重现PD的病理分期。我们的研究结果表明，低剂量长期和灌胃鱼藤酮可诱导α -突触核蛋白在野生型小鼠上述所有神经系统结构中积累。此外，我们还在ENS和DMV中观察到炎症和α -突触核蛋白磷酸化。高效液相色谱分析显示，在治疗1.5个月后，全身血液和中枢神经系统中没有鱼藤酮水平（检测限[鱼藤酮]<20 nM），线粒体复合物I测量显示没有全身复合物I抑制。这些改变是连续的，仅出现在突触连接的神经结构中，治疗时间依赖性，并伴有炎症体征和运动功能障碍。这些结果强烈提示，农药对ENS的局部作用可能足以诱导PD样进展，并重现PD分期的神经解剖学和神经化学特征。它为环境因素如何触发PD提供了新的见解，并提出了PD可能在整个中枢神经系统中传播的跨突触机制。
In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.
登录
查看更多内容
影响因子：
3
作者：
Kadar, Andrea;Wittmann, Gabor;Liposits, Zsolt;Fekete, Csaba
通讯作者：
Fekete, Csaba
影响因子：
9.9
作者：
Abbott, RD;Petrovitch, H;Ross, GW
通讯作者：
Ross, GW
影响因子：
4.7
作者：
Inden, Masatoshi;Kitamura, Yoshihisa;Shimohama, Shun
通讯作者：
Shimohama, Shun
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T
影响因子：
6.1
作者：
Drolet, Robert E.;Cannon, Jason R.;Greenamyre, J. Timothy
通讯作者：
Greenamyre, J. Timothy