Microglial activation in perinatal rabbit brain induced by intrauterine inflammation:: Detection with 11C-(R)-PK11195 and small-animal PET
Microglial activation in perinatal rabbit brain induced by intrauterine inflammation:: Detection with 11C-(R)-PK11195 and small-animal PET
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DOI：
10.2967/jnumed.106.038539
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发表时间：
2007-06-01
影响因子：
9.3
通讯作者：
Chugani, Diane C.
中科院分区：
文献类型：
--
作者：
Kannan, Sujatha;Saadani-Makkil, Fadoua;Chugani, Diane C.
宫内感染可导致胎儿炎症反应综合征，该综合征已被认为是围产期脑损伤的原因之一，导致脑室周围白质软化(PVL)和脑性瘫痪。在PVL患者的尸检标本和新生儿缺氧和缺血模型中，已经注意到激活的小胶质细胞的存在。激活的小胶质细胞可通过释放炎性细胞因子和产生兴奋性毒性代谢物而导致少突胶质细胞损伤和脑白质损伤。我们假设，在宫内暴露于内毒素会导致胎儿大脑中小胶质细胞的激活，这可以通过C-11-(R)-PK11195(1-[2-chlorophenyl]N-methyl-N-[1-methylpropyl]-3-isoquinoline(氨甲酰胺)-一种正电子发射配体结合激活的小胶质细胞中的苯二氮卓受体位点-使用小动物PET进行体内监测。方法：对妊娠新西兰大白兔进行剖腹手术，于妊娠第28天沿子宫全长注射大肠杆菌脂多糖20和30 mg/kg。仔鼠于足月(31d)自然出生，静脉注射C-11-(R)-PK11195后用小动物PET扫描，出生后第1天行MRI扫描，计算示踪剂注射后每隔10分钟、60分钟全脑的标准摄取值(SUV)。扫描后对幼鼠实施安乐死，并固定、切片并使用生物素标记的番茄凝集素对小胶质细胞进行染色。结果：与年龄匹配的对照组相比，内毒素治疗组的幼鼠C-11-(R)-PK11195的脑保留率增加，这是由SUV的斜率随时间的显著差异确定的。免疫组织化学染色显示，宫内注射内毒素后，仔兔脑室周围区和海马区活化的小胶质细胞呈剂量依赖性变化(数量增加和形态变化)。结论：宫内炎症导致小胶质细胞活化，可能参与围产期脑损伤和脑白质损伤的发生发展。
Intrauterine infection can lead to a fetal inflammatory response syndrome that has been implicated as one of the causes of perinatal brain injury leading to periventricular leukomalacia (PVL) and cerebral palsy. The presence of activated microglial cells has been noted in autopsy specimens of patients with PVL and in models of neonatal hypoxia and ischemia. Activated microglial cells can cause oligodendrocyte damage and white matter injury by release of inflammatory cytokines and production of excitotoxic metabolites. We hypothesized that exposure to endotoxin in utero leads to microglial activation in the fetal brain that can be monitored in vivo by C-11-(R)-PK11195 (1-[2-chlorophenyl]N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide)- a positron-emitting ligand that binds peripheral benzodiazepine receptor sites in activated microglia-using small-animal PET. Methods: Pregnant New Zealand White rabbits underwent laparotomy and were injected with 20 and 30 mu g/kg of Escherichia coli lipopolysaccharide along the length of the uterus on day 28 of gestation. The pups were born spontaneously at term (31 d) and were scanned using small-animal PET after intravenous administration of C-11-(R)-PK11195 and by MRI on postnatal day 1. The standard uptake values (SUVs) of the tracer were calculated for the whole brain at 10-min intervals for 60 min after tracer injection. The pups were euthanized after the scan, and brains were fixed, sectioned, and stained for microglial cells using biotinylated tomato lectin. Results: There was increased brain retention of C-11-(R)-PK11195 - as determined by a significant difference in the slope of the SUV over time-in the endotoxin-treated pups when compared with that of age-matched controls. Immunohistochemical staining showed dose-dependent changes in activated microglia (increased number and morphologic changes) in the periventricular region and hippocampus of the brain of newborn rabbit pups exposed to endotoxin in utero. Conclusion: Intrauterine inflammation leads to activation of microglial cells that may be responsible for the development of brain injury and white matter damage in the perinatal period.