Ling Z D, Chang Q, Lipton J W, Tong C W, Landers T M, Carvey P M
Department of Pharmacology, 1735 West Harrison Street, Room 410, Rush University Medical Center, Chicago, IL 60612, USA.
Neuroscience. 2004;124(3):619-28. doi: 10.1016/j.neuroscience.2003.12.017.
We previously reported that injection of the Gram (-) bacteriotoxin, lipopolysaccharide (LPS), into gravid females at embryonic day 10.5 led to the birth of animals with fewer than normal dopamine (DA) neurons when assessed at postnatal days (P) 10 and 21. To determine if these changes continued into adulthood, we have now assessed animals at P120. As part of the previous studies, we also observed that the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) was elevated in the striatum, suggesting that these animals would be more susceptible to subsequent DA neurotoxin exposure. In order to test this hypothesis, we injected (at P99) 6-hydroxydopamine (6OHDA) or saline into animals exposed to LPS or saline prenatally. The results showed that animals exposed to prenatal LPS or postnatal 6OHDA alone had 33% and 46%, respectively, fewer DA neurons than controls, while the two toxins combined produced a less than additive 62% loss. Alterations in striatal DA were similar to, and significantly correlated with (r(2)=0.833) the DA cell losses. Prenatal LPS produced a 31% increase in striatal TNFalpha, and combined exposure with 6OHDA led to an 82% increase. We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson's disease.
我们之前报道过，在胚胎第10.5天向怀孕雌性动物注射革兰氏阴性菌毒素脂多糖（LPS），在出生后第10天和第21天评估时，所产动物的多巴胺（DA）神经元数量少于正常水平。为了确定这些变化是否会持续到成年期，我们现在对出生后第120天的动物进行了评估。作为之前研究的一部分，我们还观察到纹状体中促炎细胞因子肿瘤坏死因子α（TNFα）升高，这表明这些动物对随后的DA神经毒素暴露更敏感。为了验证这一假设，我们在出生后第99天向产前暴露于LPS或生理盐水的动物注射6-羟基多巴胺（6OHDA）或生理盐水。结果显示，单独产前暴露于LPS或产后暴露于6OHDA的动物，其DA神经元数量分别比对照组少33%和46%，而两种毒素联合作用导致的损失小于相加效应，为62%。纹状体中DA的变化与DA细胞损失相似，且显著相关（r² = 0.833）。产前LPS使纹状体TNFα增加31%，与6OHDA联合暴露导致增加82%。我们得出结论，产前暴露于LPS会导致长期的酪氨酸羟化酶免疫反应（THir）细胞损失，并伴有炎症状态，这会导致后续神经毒素暴露后进一步的DA神经元损失。结果表明，产前暴露于LPS的个体，比如其母亲患有细菌性阴道炎时可能发生的情况，患帕金森病的风险会增加。
