DJ-1缺失增加出生前脂多糖暴露引起的出生后小鼠多巴胺能神经元丢失(英文)

DJ-1 deficiency synergistically increase dopaminergic neuron loss in mice prenatally exposed to lipopolysaccharide

目的:观察DJ-1缺失和出生前脂多糖(lipopolysaccharide,LPS)暴露对出生后小鼠多巴胺能(dopam-inergic,DA)系统和神经炎症的影响。方法:妊娠第10.5 d DJ-1基因敲除的小鼠腹腔注射脂多糖(10,000 EU/kg体重)后自然分娩的后代在4月和14月龄时处死。免疫组织化学染色结合体视学计数定量黑质酪氨酸羟化酶(Tyrosine hydroxylase,TH)和CD11b阳性细胞数量。高效液相色谱法测定纹状体DA代谢物水平。免疫荧光法测定TNF-α和IL-1β蛋白水平。结果:4月和14月龄的DJ-1基因敲除的小鼠均没有明显的DA神经元减少和脑内神经炎症改变。出生前接触过LPS的4月和14月龄野生型小鼠,黑质DA能神经元分别减少13.6%和23.1%,纹状体DA含量分别减少19.0%和26.2%,同时神经炎症改变明显。出生前接触过LPS的4月和14月龄DJ-1基因敲除小鼠,黑质DA能神经元分别减少22.5%和35.4%,纹状体DA含量分别减少34.3%和39.3%,同时脑内炎症反应更明显。结论:以上结果提示遗传因素缺失和环境因素可能共同引发帕金森病发生,进一步验证了帕金森病多因素损伤引发的发病假说。

Objective： To investigate the consequences of both DJ-1 knock out（KO） and prenatal lipopolysaccharide（LPS） exposure on postnatal central dopaminergic（DA） function and neuroinflammation.Methods： Gravid DJ-1 KO mice received a single intraperitoneal injection of LPS（10,000 EU/kg） at embryonic day 10.5 and the pups were delivered.After 4 or 14 months,the mice were sacrificed and brain samples were harvested.Tyrosine hydroxylase（TH） and CD11b immunohistochemistry was performed for stereology study.High performance liquid chromatography（HPLC） for striatal DA biochemistry and multiplex cytokine（TNF-α,IL-1β） assays for regional brain tissue were also performed.Results： DJ-1 KO mice（4 and 14 months） had no observable DA neuron loss and no neuroinflammation.Prenatal LPS exposure produced a statistically significant 13.6% loss of DA neurons that was more pronounced in the 14-month WT animals（23.1%）.Prenatal LPS exposure reduced postnatal striatal DA by 19.0% in 4-month and 26.2% in 14-month animals,respectively.Prenatal LPS exposure produced overt neuroinflammation in WT animals.Prenatal LPS exposure led to a 22.5% loss of DA neurons at 4 months and 35.4% loss at 14 months in DJ-1 deficiency animals.And striatal DA was reduce by 34.3% at 4 months and was further reduced at 14 months（39.3%）.Prenatal LPS exposure produced pronounced neuroinflammation in DJ-1 deficiency animals.Conclusion： The results,consistent with the multiple-hit hypotheses of PD,suggest that genetic deficiencies unable to produce PD-like changes may do so in the presence of environmental insults.