Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update
Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update
复制标题
DOI：
10.1007/s11064-017-2282-0
复制
发表时间：
2017-07-01
影响因子：
4.4
通讯作者：
Moshe, Solomon L.
中科院分区：
文献类型：
--
作者：
Galanopoulou, Aristea S.;Mowrey, Wenzhu B.;Moshe, Solomon L.
婴儿痉挛是West综合征的典型发作，West综合征是一种预后不良的婴儿癫痫性脑病。有一个越来越多的需要，以确定更有效和更好的耐受性治疗婴儿痉挛症。我们已经优化了婴儿痉挛症的大鼠模型，由于结构性病因，多次打击大鼠模型，治疗发现。在这里，我们测试了三种化合物在多次打击模型中痉挛诱导后给药的疗效和耐受性。具体而言，通过右脑内注射阿霉素和脂多糖诱导出生后第3天（PN 3）雄性Sprague-Dawley大鼠。在PN 5，腹膜内（i. p.）给予对氯苯丙氨酸。每日监测体重和发育里程碑，并间歇性视频监测大鼠。遵循盲法、随机化、媒介物对照研究设计。半胱天冬酶1抑制剂VX-765（50-200 mg/kg i. p.）和GABA（B）受体抑制剂CGP 35348（12.5-100 mg/kg i. p.）在PN 4，每种药物在不同的组群中作为单次腹膜内注射给药，使用剂量-和时间-反应设计，间歇监测直至PN 5。在PN 3 -10之间每天给予17 β-雌二醇（40 ng/g/天皮下注射），并进行间歇监测直至PN 12。所有治疗均未显示对痉挛的急性或延迟效应，但所有治疗均耐受良好。我们讨论了治疗发现和挑战的复制试验的影响。
Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide. On PN5 p-chlorophenylalanine was given intraperitoneally (i.p.). Daily monitoring of weights and developmental milestones was done and rats were intermittently video monitored. A blinded, randomized, vehicle-controlled study design was followed. The caspase 1 inhibitor VX-765 (50-200 mg/kg i.p.) and the GABA(B) receptor inhibitor CGP35348 (12.5-100 mg/kg i.p.) each was administered in different cohorts as single intraperitoneal injections on PN4, using a dose- and time-response design with intermittent monitoring till PN5. 17 beta-estradiol (40 ng/g/day subcutaneously) was given daily between PN3-10 and intermittent monitoring was done till PN12. None of the treatments demonstrated acute or delayed effects on spasms, yet all were well tolerated. We discuss the implications for therapy discovery and challenges of replication trials.