BACKGROUND Chorioamnionitis from ascending bacterial infection through the endocervix is a potential risk factor for cerebral palsy. Tetrahydrobiopterin, an essential cofactor for nitric oxide synthase (NOS) and amino acid hydroxylases, when augmented in the fetal brain, prevents some of the cerebral palsy-like deficits in a rabbit hypoxia-ischemia model. OBJECTIVES To study the effect of lipopolysaccharide (LPS)-induced intrauterine inflammation in preterm gestation on motor deficits in the newborn, and whether biosynthesis of tetrahydrobiopterin or inflammatory mediators is affected in the fetal brain. METHODS Pregnant rabbits at 28 days gestation (89% term) were administered either saline or LPS into both endocervical openings. One group underwent spontaneous delivery, and neurobehavioral tests were performed at postnatal day (P) 1 and P11, with some kits being sacrificed at P1 for histological analysis. Another group underwent Cesarean section 24 h after LPS administration. Gene sequences for rabbit biosynthetic enzymes of tetra-hydrobiopterin pathways were determined and analyzed in addition to cytokines, using quantitative real-time polymerase chain reaction. RESULTS Exposure to 200 μg/kg/mL LPS caused a locomotion deficit and mild hypertonia at P1. By P11, most animals turned into normal-appearing kits. There was no difference in neuronal cell death in the caudate between hypertonic and nonhypertonic kits at P1 (n = 3-5 in each group). Fetal brain GTP cyclohydrolase I was increased, whereas sepiapterin reductase and 6-pyruvoyltetrahydropterin synthase were decreased, 24 h after LPS administration. Neuronal NOS was also increased. Regardless of the position in the uterus or the brain region, expression of TNF-α and TGF-β was decreased, whereas that of IL-1β, IL-6, and IL-8 was increased (n = 3-4 in each group). CONCLUSIONS This is the first study using an ascending LPS-induced intrauterine inflammation model in rabbits, showing mostly transient hypertonia and mainly locomotor deficits in the kits. Not all proinflammatory cytokines are increased in the fetal brain following LPS administration. Changes in key tetrahydro-biopterin biosynthetic enzymes possibly indicate different effects of the inflammatory insult.

中文翻译：

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上行脂多糖诱导的近期兔宫内炎症导致新生儿神经行为缺陷。

背景 通过宫颈内膜上行细菌感染引起的绒毛膜羊膜炎是脑瘫的潜在危险因素。四氢生物蝶呤是一氧化氮合酶 (NOS) 和氨基酸羟化酶的必需辅助因子，当在胎儿大脑中得到增强时，可防止兔缺氧缺血模型中的一些脑瘫样缺陷。目的 研究早产时脂多糖 (LPS) 诱导的宫内炎症对新生儿运动障碍的影响，以及胎儿脑中四氢生物蝶呤或炎症介质的生物合成是否受到影响。方法 对妊娠 28 天（89% 足月）的孕兔进行生理盐水或 LPS 注射到两个宫颈管开口中。一组进行自然分娩，并在产后第 (P) 1 天和第 11 天进行神经行为测试，在 P1 处牺牲了一些套件用于组织学分析。另一组在 LPS 给药后 24 小时接受剖腹产。除了细胞因子外，还使用定量实时聚合酶链反应确定和分析了兔四氢生物蝶呤途径生物合成酶的基因序列。结果 暴露于 200 μg/kg/mL LPS 在 P1 导致运动缺陷和轻度肌张力亢进。到 P11，大多数动物都变成了正常的幼崽。在 P1（每组 n = 3-5），高渗和非高渗套件之间的尾状核神经元细胞死亡没有差异。在 LPS 给药后 24 小时，胎脑 GTP 环水解酶 I 增加，而 sepiapterin 还原酶和 6-丙酮酰四氢蝶呤合酶减少。神经元 NOS 也增加了。无论在子宫或脑区的哪个位置，TNF-α和TGF-β的表达均降低，而IL-1β、IL-6和IL-8的表达增加（每组n = 3-4 ). 结论 这是第一项在兔子中使用升序 LPS 诱导的宫内炎症模型的研究，显示试剂盒中主要是短暂性肌张力亢进和主要是运动缺陷。在 LPS 给药后，并非所有促炎细胞因子在胎儿大脑中都会增加。关键四氢生物蝶呤生物合成酶的变化可能表明炎症损伤的不同影响。在工具包中显示出主要是短暂性肌张力亢进和主要是运动缺陷。在 LPS 给药后，并非所有促炎细胞因子在胎儿大脑中都会增加。关键四氢生物蝶呤生物合成酶的变化可能表明炎症损伤的不同影响。在工具包中显示出主要是短暂性肌张力亢进和主要是运动缺陷。在 LPS 给药后，并非所有促炎细胞因子在胎儿大脑中都会增加。关键四氢生物蝶呤生物合成酶的变化可能表明炎症损伤的不同影响。