Validation of the rat model of cryptogenic infantile spasms
Validation of the rat model of cryptogenic infantile spasms
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DOI：
10.1111/j.1528-1167.2011.03220.x
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发表时间：
2011-09-01
期刊：
影响因子：
5.6
通讯作者：
Velisek, Libor
中科院分区：
文献类型：
--
作者：
Chachua, Tamar;Yum, Mi-Sun;Velisek, Libor
目的：确定一种新的隐源性婴儿痉挛模型，包括产前用倍他米松启动和产后用 N-甲基-D-天冬氨酸 (NMDA) 引发痉挛，是否对慢性促肾上腺皮质激素 (ACTH) 治疗有反应，并具有与人类婴儿痉挛相似的脑电图 (EEG) 特征、治疗效果和行为障碍。使用妊娠第15天。一名受试者在出生后第 10 天和第 15 天之间用 NMDA 在单次或多次治疗中引发痉挛。将痉挛的表达与产前注射盐水的对照进行比较。在倍他米松引发的大鼠中测定了相关治疗（促肾上腺皮质激素、氨己烯酸、甲泼尼龙、雷帕霉素）的效果。在痉挛后的大鼠中，在 P20-22 时在开放场地和高架十字迷宫中进行行为评估。 主要发现：与对照组相比，P10-15（大鼠“婴儿”期）的 NMDA 在产前倍他米松暴露的大脑中显着更早地触发痉挛，并且触发痉挛的数量更多。与人类的情况类似，痉挛是成群发生的。反复触发痉挛与发作期脑电图电减量和发作间期大幅波有关，这可能是大鼠高心律失常的一种变体。随机实验中的慢性 ACTH 治疗和甲基泼尼松龙的长期预处理可显着抑制与人类状况相似的痉挛次数。用氨己烯酸（而非雷帕霉素）预处理可以抑制痉挛。多次痉挛后会出现显着的行为变化。意义：婴儿痉挛模型在症状学、脑电图、药理反应和长期结果方面与人类状况具有显着的相似性。因此，该模型可用于寻找新颖且更有效的婴儿痉挛症治疗方法。
Purpose: To determine whether a new model of cryptogenic infantile spasms consisting of prenatal priming with betamethasone and postnatal trigger of spasms by N-methyl-D-aspartate (NMDA) responds to chronic adrenocorticotropic hormone (ACTH) treatment, and has electroencephalography (EEG) signature, efficacy of treatments, and behavioral impairments similar to those in human infantile spasms.Methods: Rats prenatally primed with betamethasone on gestational day 15 were used. Spasms were triggered with NMDA between postnatal days (P) 10 and 15 in a single session or in multiple sessions in one subject. The expression of spasms was compared to prenatally saline-injected controls. Effects of relevant treatments (ACTH, vigabatrin, methylprednisolone, rapamycin) were determined in betamethasone-primed rats. In the rats after spasms, behavioral evaluation was performed in the open field and elevated plus maze on P20-22.Key Findings: NMDA at P10-15 (the rat "infant" period) triggers the spasms significantly earlier and in greater numbers in the prenatal betamethasone-exposed brain compared to controls. Similar to human condition, the spasms occur in clusters. Repeated trigger of spasms is associated with ictal EEG electrodecrements and interictal large-amplitude waves, a possible rat variant of hypsarrhythmia. Chronic ACTH treatment in a randomized experiment, and chronic pretreatment with methylprednisolone significantly suppress the number of spasms similar to the human condition. Pretreatment with vigabatrin, but not rapamycin, suppressed the spasms. Significant behavioral changes occurred following multiple bouts of spasms.Significance: The model of infantile spasms has remarkable similarities with the human condition in semiology, EEG, pharmacologic response, and long-term outcome. Therefore, the model can be used to search for novel and more effective treatments for infantile spasms.