The Cain Foundation Laboratories, The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, United States; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, United States.
Epilepsy Behav. 2021 Mar;116:107786. doi: 10.1016/j.yebeh.2021.107786. Epub 2021 Feb 3.
Studies were undertaken to evaluate the effectiveness of Acthar® Gel (repository corticotropin injection [RCI]) in the tetrodotoxin (TTX) model of early-life-induced epileptic spasms. Repository corticotropin injection (RCI) is widely used in the United States to treat infantile spasms. A major component of RCI is N25 deamidated ACTH. Additionally, we hoped to provide some insight into the possible role circulating corticosteroids play in spasm cessation by comparing the RCI dose-response relationships for spasm suppression to RCI-induced corticosterone release from the adrenal gland. Spasms were induced by chronic TTX infusion into the neocortex beginning on postnatal day 11. Repository corticotropin injection (RCI) dosages were between 8 and 32 IU/kg/day. Drug titration protocols were used, and comparisons were made to injections of a vehicle gel. Video/EEG recordings (24/7) monitored the drug's effects continuously for up to 2 months. Tetrodotoxin (TTX)-infused control rats were monitored for the same period of time. In separate experiments, the same dosages of RCI were given to rats and 1 h later plasma was collected and assayed for corticosterone. A parallel study compared the effects of 1-day and 10-day RCI treatments on circulating corticosterone. Results showed that RCI was ineffective at dosages of 8, 12, and 16 IU/kg/day but eliminated spasms in 66% of animals treated with 24 or 32 IU/kg/day. Treating animals with 32 IU/kg/day alone produced the same degree of spasms suppression as observed during the titration protocols. In rats that had hypsarrhythmia-like activity, RCI eliminated this abnormal interictal EEG pattern in all rats that became seizure-free. In terms of plasma corticosterone, 1- and 10-day treatments with RCI produced similar increases in this hormone and the levels increased linearly with increasing dosages of RCI. This stood in sharp contrast to the sigmoid-like dose-response curve for decreases in spasm counts. Our results further validate the TTX model as relevant for the study of infantile spasms. The model should be useful for investigating how RCI acts to eliminate seizures and hypsarrhythmia. Dose-response results suggest that either very high concentrations of circulating corticosteroids are required to abolish spasms or RCI acts through a different mechanism.
研究旨在评估 Acthar® Gel（促肾上腺皮质激素储存制剂[RCI]）在早发性生命诱导的癫痫痉挛的肉毒杆菌毒素（TTX）模型中的有效性。促肾上腺皮质激素储存制剂（RCI）在美国被广泛用于治疗婴儿痉挛。RCI 的主要成分是 N25 去酰胺 ACTH。此外，我们希望通过比较 RCI 对肾上腺皮质酮释放的剂量反应关系与 RCI 对痉挛的抑制作用，来了解循环皮质激素在痉挛停止中可能发挥的作用。从出生后第 11 天开始，通过慢性 TTX 输注到新皮层来诱导痉挛。RCI 剂量为 8 至 32IU/kg/天。使用药物滴定方案，并与载体凝胶的注射进行比较。视频/EEG 记录（24/7）连续监测药物的作用长达 2 个月。TTX 输注对照大鼠在相同的时间段内进行监测。在单独的实验中，给大鼠相同剂量的 RCI，1 小时后收集血浆并测定皮质酮。一项平行研究比较了 1 天和 10 天 RCI 治疗对循环皮质酮的影响。结果表明，RCI 在 8、12 和 16IU/kg/天的剂量下无效，但在 24 或 32IU/kg/天的剂量下治疗的 66%的动物中消除了痉挛。仅用 32IU/kg/天治疗动物产生了与滴定方案中观察到的相同程度的痉挛抑制。在具有高度节律性样活动的大鼠中，RCI 消除了所有无癫痫发作大鼠的这种异常间脑 EEG 模式。就血浆皮质酮而言，RCI 治疗 1 天和 10 天产生了这种激素的相似增加，并且水平随 RCI 剂量的增加呈线性增加。这与痉挛计数减少的类似 S 形剂量反应曲线形成鲜明对比。我们的结果进一步验证了 TTX 模型与婴儿痉挛的研究相关。该模型应该有助于研究 RCI 如何消除癫痫发作和高度节律性。剂量反应结果表明，要么需要非常高浓度的循环皮质激素来消除痉挛，要么 RCI 通过不同的机制起作用。
