【摘要】 目的:探讨低剂量鱼藤酮持续灌胃致中脑多巴胺能神经元损伤的可能机制。方法:将50只老年雄性C57小鼠随机分为模型组和对照组各25只,2组均给予连续灌胃12周,模型组灌注0.01 mL/g鱼藤酮氯仿溶液,对照组灌注0.01 mL/g氯仿溶液。在灌胃前、灌胃6周、12周时对肠、胸段脊髓、中脑行α-突触核蛋白(α-Syn)、硫磺素S(ThS)、酪氨酸羟化酶(TH)等免疫组化染色。灌胃12周时采用透射电镜观察2组黑质神经元超微结构。结果:免疫组化染色提示灌胃6周时模型组小肠内、胸段脊髓处α-Syn的表达较对照组明显增加,且ThS表达比例增多,中脑处α-Syn及TH阳性细胞数无明显差异(P>0.05);灌胃12周时,模型组中脑α-Syn的表达较对照组明显增多,TH阳性细胞数较对照组减少(P=0.011)。灌胃12周后透射电镜显示模型组小鼠黑质部可见细胞膜、线粒体、内质网不规则肿胀,细胞核形态各异,部分神经元溶解坏死,数目减少,对照组未见明显改变。结论:持续鱼藤酮灌胃可能首先在小肠神经丛局部形成α-Syn多聚体,再通过类朊蛋白途径沿着神经传导通路播散至脑内而导致多巴胺神经元损伤。更多还原

【Abstract】 Objective:To explore the mechanism of dopaminergic neuron damage induced by constant intragastric administration of low-dose rotenone. Methods: Fifty aged male mice were randomly divided into Parkinson disease(PD) model group and control group. The mice in PD model group were administrated 0.01 mL/g rotenone by gavage while the mice in control group were administrated 0.01 mL/g chloroform. Before treatment and 6 weeks, as well as 12 weeks after treatment, alpha-synuclein(α-Syn), Thioflavin S(ThS) and tyrosine hydroxylase(TH) were detected in neurons from gastrointestinal tract, thoracic spinal cord and midbrain of both the control and treated animals. Simultaneously, ultrastructural changes were observed by electron microscopy 12 weeks after treatment. Results: Six weeks after treatment, immunofluorescence demonstrated that α-Syn and ThS were increased in intestinal intramural plexus and thoracic spinal cord in the PD model group compared to the controls while the expression of α-Syn and number of TH positive neurons in midbrain did not show any significant changes(P>0.05). However, 12 weeks after treatment, immunofluorescence showed that there was an increase in α-Syn and an significant decrease in TH positive neurons in the midbrain(P=0.011) in the model group compared with those in the controls. Moreover, electron microscopy showed a lot of abnormalities in the PD model group, such as the swollenness of cell membrane, mitochondria and endoplasmic reticulum, alterations of nuclei, and necrosis of neurons in the substantia nigra, in a sharp contrast to the normality in the.control group. Conclusion: Dopaminergic neuron damage was observed in mouse brain after constant intragastric administration of low-dose rotenone, probably mediated by the spread of synuclein aggregates formed in gastrointestinal plexues into brain by prion-like transmission.更多还原