Ling Zaodung, Zhu Yuangui, Tong Chong Wai, Snyder Joshua A, Lipton Jack W, Carvey Paul M
Department of Pharmacology, Rush University Medical Center, Cohn Research Building, Suite 406, 1735 W. Harrison St., Chicago, IL 60612, USA.
Exp Neurol. 2009 Apr;216(2):312-20. doi: 10.1016/j.expneurol.2008.12.004. Epub 2008 Dec 16.
We previously demonstrated that in utero exposure to the bacteriotoxin lipopolysaccharide (LPS) led to the birth of rat pups with fewer than normal dopamine (DA) neurons. These animals exhibited significant neuroinflammation in the nigrostriatal pathway creating the possibility that they could exhibit further, progressive DA neuron loss over their lives. To study this possibility, we injected gravid female rats i.p. at 10,000 endotoxin units (EUs) of LPS per kg or saline at embryonic (E) day 10.5 and assigned pups to sacrifice groups at 4, 14 and 17 months such that littermates were sacrificed at each end point. The effects of prenatal LPS on DA cell counts and striatal DA were significantly reduced relative to controls whereas DA activity and numbers of activated microglia (OX-6ir cell) were statistically increased. However, the progressive DA neuron loss was parallel to that of the controls suggesting that prenatal LPS does not produce an accelerated rate of DA neuron loss. Interestingly, locomotor activity was increased after 3 months in animals exposed to LPS prenatally, but by 16 months, was significantly reduced relative to controls. Additionally, animals exposed to LPS prenatally exhibited Lewy body-like inclusions that were first seen in 14 month old animals. These data broadly support previous studies demonstrating that prenatal exposure to LPS, as frequently occurs in humans as part of Bacterial Vaginosis, leads to the birth of animals with fewer than normal DA neurons. The progressive DA neuron loss seen in these animals is, however, primarily a result of normal aging.
我们之前证明，子宫内暴露于细菌毒素脂多糖（LPS）会导致出生的大鼠幼崽多巴胺（DA）神经元数量低于正常水平。这些动物在黑质纹状体通路中表现出明显的神经炎症，这使得它们有可能在一生中进一步出现渐进性DA神经元丢失。为了研究这种可能性，我们在胚胎（E）第10.5天给怀孕的雌性大鼠腹腔注射每千克10000内毒素单位（EUs）的LPS或生理盐水，并将幼崽分配到4、14和17个月的处死组，以便在每个终点处死同窝幼崽。与对照组相比，产前LPS对DA细胞计数和纹状体DA水平产生的影响显著降低，而DA活性和活化小胶质细胞（OX-6ir细胞）数量在统计学上增加。然而，DA神经元渐进性丢失与对照组平行表明产前LPS不会导致DA神经元丢失加速。有趣地是，产前暴露于LPS的动物在3个月后运动活性增加，但到16个月时相对于对照组显著降低。此外，产前暴露于LPS的动物表现出路易体样包涵体，最早在14个月龄的动物中发现。这些数据广泛支持先前的研究，即产前暴露于LPS（人类细菌性阴道病中经常发生）会导致出生的动物DA神经元数量低于正常水平。然而，这些动物中出现的DA神经元渐进性丢失主要是正常衰老的结果。
