Retinoic acid induced myelomeningocele in fetal rats: Characterization by histopathological analysis and magnetic resonance imaging
Retinoic acid induced myelomeningocele in fetal rats: Characterization by histopathological analysis and magnetic resonance imaging
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DOI：
10.1016/j.expneurol.2005.03.011
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Flake, AW
中科院分区：
文献类型：
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作者：
Danzer, E;Schwarz, U;Flake, AW
通过叶酸预防人类神经管缺陷和对脊髓脊膜膨出（MMC）进行胎儿手术干预的可能性重新引起了人们对脊柱裂分子途径和病理生理学的兴趣。需要动物模型来评估这种病变的早期发育生物学和病理生理学。本研究的目的是开发和表征MMC的非手术大鼠模型。在E10时，用不同剂量的溶于橄榄油的视黄酸（RA）灌胃Sprague-Dawley大鼠（母体n=55，胎仔n=505）。对照动物仅接受橄榄油（母体n=20，胎仔n=265）或未接受橄榄油（母体n=5，胎仔n=63）。通过详细的组织病理学和MRI分析胎仔。总体而言，60.7%（307/505）的RA暴露胎仔发生了孤立的MMC，对照组无一例发生。组织学证实了在人类MMC中观察到的整个严重程度范围，从暴露具有完整神经元件的脊髓到完全脊髓破坏。MMC胎儿大脑的MRI证实了与Arnold-Chiari畸形人类相似的结构机会，包括小脑向下移位至枕骨大孔上方，发育中的髓质受压进入小的后颅窝。结论：RA诱导的MMC大鼠模型在发育和解剖学上与人MMC相似。这种相对有效和具有成本效益的MMC模型应有利于MMC的发育生物学和病理生理学的调查，并可能是有用的产前治疗的进一步战略的评估。(c)2005年爱思唯尔公司All rights reserved.
The prevention of human neural tube defects by folic acid administration and the potential for fetal surgical intervention for myelomeningocele (MMC) have renewed interest in the molecular pathways and pathophysiology of spina bifida. Animal models for assessment of the early developmental biology and pathophysiology of this lesion are needed. The goal of this study was to develop and characterize a non-surgical rat model of MMC. Time-dated Sprague-Dawley rats were gavage fed different doses of retinoic acid (RA) dissolved in olive oil at E10 (maternal n=55, fetal n=505). Control animals received olive oil alone (maternal n=20, fetal n=265) or were untreated (maternal n=5, fetal n=63). Fetuses were analyzed by detailed histopathology and MRI. Overall, isolated MMC occurred in 60.7% (307/505) of RA-exposed fetuses and no controls. Histopathology confirmed the entire spectrum of severity observed in human MMC, ranging from exposure of the cord with intact neural elements to complete cord destruction. MRI of the brain of MMC fetuses confirmed structural chances similar to humans with Arnold-Chiari malformation, including downward displacement of the cerebellum to just above the foramen magnum and compression of the developing medulla into a small posterior fossa. In Conclusion, the RA-induced rat model of MMC is developmentally and anatomically analogous to human MMC. This relatively efficient and cost-effective model of MMC should facilitate investigation of the developmental biology and pathophysiology of MMC, and may be useful for the evaluation of further strategies for prenatal treatment. (c) 2005 Elsevier Inc. All rights reserved.