Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life.
Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life.
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DOI：
10.1016/j.nbd.2011.07.011
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发表时间：
2011-12
影响因子：
6.1
通讯作者：
Cai, Zhengwei
中科院分区：
文献类型：
--
作者：
Fan, Lir-Wan;Tien, Lu-Tai;Lin, Rick C. S.;Simpson, Kimberly L.;Rhodes, Philip G.;Cai, Zhengwei
关键词：
有人提出，生命早期的脑部炎症在成年后神经退行性疾病的发展中发挥着重要作用。为了检验这一假设，我们使用脂多糖 (LPS) 暴露的新生大鼠模型（1,000 EU/g 体重，P5 时脑内注射）来产生脑部炎症。到 P70 时，当 LPS 诱导的行为缺陷自发恢复时，通过皮下微型泵输注每天 1.25 mg/kg 的剂量，用鱼藤酮（一种常用的杀虫剂）对动物进行攻击，持续 14 天。这种鱼藤酮治疗方案通常不会对正常成年大鼠的行为产生毒性作用。我们的结果表明，新生儿脂多糖暴露增加了黑质纹状体多巴胺能神经元在以后的生活中对鱼藤酮神经毒性的脆弱性。鱼藤酮治疗会导致暴露于新生儿 LPS 的大鼠出现运动神经行为障碍，但不会导致未暴露于新生儿 LPS 的大鼠出现运动神经行为障碍。鱼藤酮会导致接触新生 LPS 的大鼠黑质中酪氨酸羟化酶免疫反应性神经元的损失，并降低纹状体中线粒体复合物 I 的活性，但在未接触过 LPS 的大鼠中则不然。新生儿LPS暴露以及后来暴露于鱼藤酮减少了逆行标记的黑质纹状体多巴胺能投射神经元。目前的研究表明，围产期脑部炎症可能会增加成人对神经退行性疾病的易感性，这些神经退行性疾病是由环境毒素在通常无毒或亚毒剂量下引发的。我们的模型可能有助于研究非家族性帕金森病的发病机制和潜在治疗方法的开发。
Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1,000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson’s disease and the development of potential therapeutic treatments.
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影响因子：
4.8
作者：
Fortier, ME;Joober, R;Boksa, P
通讯作者：
Boksa, P
影响因子：
2.7
作者：
Bilbo, SD;Rudy, JW;Maier, SF
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Maier, SF
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作者：
Fan, Lir-Wan;Tien, Lu-Tai;Cai, Zhengwei
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Cai, Zhengwei
影响因子：
15.1
作者：
Fan, Lir-Wan;Tien, Lu-Tai;Cai, Zhengwei
通讯作者：
Cai, Zhengwei
影响因子：
4.2
作者：
Fan, LW;Pang, Y;Cai, ZW
通讯作者：
Cai, ZW