Yum Mi-Sun, Lee Minyoung, Woo Dong-Cheol, Kim Dong Wook, Ko Tae-Sung, Velíšek Libor
Department of Pediatrics, Asan Medical Center, College of Medicine Ulsan University, Seoul, South Korea.
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea.
Epilepsy Res. 2015 Nov;117:125-32. doi: 10.1016/j.eplepsyres.2015.08.005. Epub 2015 Aug 8.
Infantile spasms (IS) is a devastating epileptic encephalopathy. The ketogenic diet (KD) has been successfully used as a treatment for IS. This study was designed to test whether beta-hydroxybutyrate (BHB), a major metabolite of the KD, is effective in an animal model of IS.
Pregnant rats received betamethasone on gestational day 15. The offspring received either single [30min prior to NMDA-triggered spasms on postnatal day (P) 15] or prolonged (three per day from P12 to P15) i.p. BHB. An additional experiment used repeated bouts of spasms on P12, P13, and P15 with randomized prolonged BHB treatment initiated after the first spasms. We determined the latency to onset of spasms and the number of spasms after the NMDA injection on P15. The rats that received randomized BHB treatment were also monitored with open field, sociability, and fear-conditioning tests and underwent in vivo (1)H MR imaging on a 9.4T MR system after NMDA-induced spasms. The acquired (1)H MR spectra were quantified using LC model.
Single-dose BHB pretreatment had no effect on spasms. In contrast, prolonged pretreatment with BHB significantly delayed the onset and decreased the frequency of spasms. In addition, randomized prolonged BHB treatment resulted in a significant reduction in number of spasms at P15. BHB treatment had no significant effect on motor activities, but significantly decreased the interactions with strangers and increased the contextual memory. On MR spectroscopic analysis of randomized prolonged BHB-treated rats at 24h after the cluster of spasms, the elevation of GABA, glutamine, glutamate, total creatine, macromolecule-plus lipids, and N-acetylaspartate levels after spasms were significantly attenuated by randomized BHB treatment (p<0.05).
Prolonged administration of BHB directly suppresses development of spasms in a rat model of IS with acute stabilization of brain metabolites. Additionally, BHB appears to decrease the interests to other rats and improve memory responses.
婴儿痉挛症（IS）是一种严重的癫痫性脑病。生酮饮食（KD）已成功用于治疗IS。本研究旨在测试KD的主要代谢产物β-羟基丁酸（BHB）在IS动物模型中是否有效。
孕鼠在妊娠第15天接受倍他米松治疗。子代在出生后第（P）15天接受单次（在NMDA触发痉挛前30分钟）或延长（从P12至P15每天三次）腹腔注射BHB。另一项实验在P12、P13和P15重复引发痉挛，并在首次痉挛后随机开始延长BHB治疗。我们测定了P15时NMDA注射后痉挛发作的潜伏期和痉挛次数。接受随机BHB治疗的大鼠还进行了旷场试验、社交能力试验和恐惧条件试验，并在NMDA诱导痉挛后在9.4T磁共振系统上进行体内氢质子磁共振成像。使用LC模型对获得的氢质子磁共振波谱进行定量分析。
单剂量BHB预处理对痉挛无影响。相比之下，BHB延长预处理显著延迟了痉挛发作并降低了痉挛频率。此外，随机延长BHB治疗导致P15时痉挛次数显著减少。BHB治疗对运动活动无显著影响，但显著减少了与陌生大鼠的互动并增强了情境记忆。对随机延长BHB治疗的大鼠在痉挛发作群后24小时进行磁共振波谱分析，随机BHB治疗显著减轻了痉挛后γ-氨基丁酸、谷氨酰胺、谷氨酸、总肌酸、大分子加脂质和N-乙酰天门冬氨酸水平的升高（p<0.05）。
延长BHB给药可直接抑制IS大鼠模型中痉挛的发展，并使脑代谢产物急性稳定。此外，BHB似乎降低了对其他大鼠的兴趣并改善了记忆反应。
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