Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice.
Long-term Effects of Multiple Glucocorticoid Exposures in Neonatal Mice.
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DOI：
10.3390/behavsci1010004
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发表时间：
2011-12-30
期刊：
影响因子：
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通讯作者：
Farber NB
中科院分区：
文献类型：
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作者：
Maloney SE;Noguchi KK;Wozniak DF;Fowler SC;Farber NB
糖皮质激素（GC）如地塞米松（DEX）或倍他米松重复给药早产儿长达一个月，作为慢性肺功能障碍的治疗。临床试验的结果表明，在这些婴儿中使用GC会导致神经运动功能和认知的长期缺陷。我们以前已经表明，在对应于人类围产期的一段时间内，小鼠单次暴露于临床相关剂量的DEX或其他GC，会导致发育中小脑神经祖细胞凋亡性细胞死亡的急剧增加。为了提供一个更接近慢性临床给药方案的模型，我们评估了重复暴露于DEX和随后GC诱导的神经元丢失可能产生的行为效应，其中新生小鼠幼崽在出生后第7、9和11天注射3.0 mg/kg DEX或生理盐水（DEX 3治疗）。成年，DEX 3处理的小鼠表现出长期的，可能是永久性的，神经运动缺陷的复杂活动轮任务，这需要高阶运动协调技能。在涉及单独小鼠队列的两项独立研究中，相对于盐水对照，DEX 3小鼠在该任务上表现出受损的表现。利用在行为测试小鼠中进行的体视学神经元计数的组织学研究表明，DEX 3处理导致小脑内部颗粒层（IGL）中的神经元数量显著减少，尽管浦肯野细胞层中的神经元数量没有变化。结果表明，多次新生儿DEX暴露可以产生与小脑IGL神经元丢失相关的精细运动协调的慢性缺陷。
Glucocorticoids (GCs) such as dexamethasone (DEX) or betamethasone are repeatedly administered for up to a month to prematurely born infants as a treatment for chronic lung dysfunction. Results of clinical trials have shown that the use of GCs in these infants induces long-term deficits in neuromotor function and cognition. We have previously shown that a single exposure to clinically relevant doses of DEX or other GCs in the mouse during a period corresponding to the human perinatal period produces a dramatic increase in apoptotic cell death of neural progenitor cells in the developing cerebellum. To provide a model approximating more chronic clinical dosing regimens, we evaluated possible behavioral effects resulting from repeated exposures to DEX and subsequent GC-induced neuronal loss where neonatal mouse pups were injected with 3.0 mg/kg DEX or saline on postnatal days 7, 9, and 11 (DEX3 treatment). Adult, DEX3-treated mice exhibited long-term, possibly permanent, neuromotor deficits on a complex activity wheel task, which requires higher-order motor co-ordination skills. DEX3 mice exhibited impaired performance on this task relative to saline controls in each of two independent studies involving separate cohorts of mice. Histopathology studies utilizing stereological neuronal counts conducted in behaviorally-tested mice showed that the DEX3 treatment resulted in a significant decrease in the number of neurons in the internal granule layer (IGL) of the cerebellum, although the number of neurons in the Purkinje cell layer were unchanged. The results suggest that multiple neonatal DEX exposures can produce chronic deficits in fine motor co-ordination that are associated with cerebellar IGL neuronal loss.