Yum Mi-Sun, Lee Minyoung, Ko Tae-Sung, Velíšek Libor
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Epilepsy Res. 2014 Nov;108(9):1492-500. doi: 10.1016/j.eplepsyres.2014.08.015. Epub 2014 Sep 2.
Infantile spasms (IS), a devastating epileptic encephalopathy of infancy, involve various etiologies associated with an unknown underlying common pathophysiology. The efficacy of adrenocorticotropic hormone (ACTH) as an IS therapy suggests a role for steroid hormones in treating IS. This study used an animal model of IS to test the efficacy of ganaxolone, a synthetic neurosteroid, promoting tonic GABAA inhibition.
The model of cryptogenic IS used in this study involved prenatal priming of rats with betamethasone (0.4 mg/kg i.p. at 08:30 and 18:30) on gestational day 15. To test the acute effects of ganaxolone, rats were pretreated with ganaxolone (10, 25, or 50mg/kg i.p.) or vehicle (β-cyclodextrin, i.p.) 30 min prior to N-methyl-d-aspartate (NMDA)-induced spasms at postnatal day 15 (P15). To mimic human conditions, another group of rats was randomly divided and repeatedly treated with ganaxolone (20mg/kg at 9:00 and 18:00 from P13-15) or vehicle after experiencing NMDA-triggered spasms at P12. Additional spasms were triggered on P13 and P15. We determined latency to the onset of spasms and the total number of spasms per 90-min observation period after the trigger at P15. On P19 and P21, behavioral tests were performed in rats with randomized repeated treatments.
The 25mg/kg and 50mg/kg doses of ganaxolone significantly delayed the onset of spasms compared with the controls, and significantly decreased the number of spasms or suppressed their incidence. Ganaxolone had significant side effects in terms of sedation: all animals with the 50mg/kg dose were sleeping during the test. Randomized ganaxolone treatment for 3 days also significantly delayed the onset and decreased the number of spasms triggered by NMDA on P15, and decreased exploratory behavior after multiple NMDA triggered spasms.
Ganaxolone significantly suppresses the development of spasms in the rat model of cryptogenic IS. This synthetic neurosteroid active in an animal model of IS might contribute to the current armamentarium to treat human IS.
婴儿痉挛症（IS）是一种严重的婴儿期癫痫性脑病，涉及多种病因，其潜在的共同病理生理学尚不清楚。促肾上腺皮质激素（ACTH）作为IS治疗方法的有效性表明类固醇激素在治疗IS中发挥作用。本研究使用IS动物模型来测试加奈索酮（一种合成神经甾体）促进GABAA受体介导的强直性抑制的疗效。
本研究中使用的隐源性IS模型涉及在妊娠第15天用倍他米松（0.4mg/kg腹腔注射，分别于08:30和18:30）对大鼠进行产前预处理。为了测试加奈索酮的急性作用，在出生后第15天（P15）给予N-甲基-D-天冬氨酸（NMDA）诱导痉挛前30分钟，用加奈索酮（10、25或50mg/kg腹腔注射）或溶剂（β-环糊精，腹腔注射）对大鼠进行预处理。为模拟人类情况，另一组大鼠在P12经历NMDA触发的痉挛后，随机分组并用加奈索酮（从P13至P15每天9:00和18:00给予20mg/kg）或溶剂反复治疗。在P13和P15再次触发痉挛。我们确定了P15触发后痉挛发作的潜伏期以及每90分钟观察期内的总痉挛次数。在P19和P21，对接受随机重复治疗的大鼠进行行为测试。
与对照组相比，25mg/kg和50mg/kg剂量的加奈索酮显著延迟了痉挛发作，并显著减少了痉挛次数或抑制了其发生率。加奈索酮在镇静方面有显著副作用：所有接受50mg/kg剂量的动物在测试期间都处于睡眠状态。随机给予加奈索酮治疗3天也显著延迟了P15时NMDA触发的痉挛发作并减少了痉挛次数，且在多次NMDA触发痉挛后减少了探索行为。
加奈索酮显著抑制隐源性IS大鼠模型中痉挛的发展。这种在IS动物模型中具有活性的合成神经甾体可能有助于目前治疗人类IS的手段。
