Choudhary Anamika, Mu Chunlong, Barrett Karlene T, Charkhand Behshad, Williams-Dyjur Christine, Marks Wendie N, Shearer Jane, Rho Jong M, Scantlebury Morris H
Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Brain Commun. 2021 Aug 28;3(4):fcab189. doi: 10.1093/braincomms/fcab189. eCollection 2021.
Infantile spasms (IS) syndrome is a catastrophic, epileptic encephalopathy of infancy that is often refractory to current antiepileptic therapies. The ketogenic diet (KD) has emerged as an alternative treatment for patients with medically intractable epilepsy, though the prospective validity and mechanism of action for IS remains largely unexplored. We investigated the KD's efficacy as well as its mechanism of action in a rodent model of intractable IS. The spasms were induced using the triple-hit paradigm and the animals were then artificially reared and put on either the KD (4:1 fats: carbohydrate + protein) or a control milk diet (CM; 1.7:1). Phosphorus magnetic resonance spectroscopy (P MRS) and head-out plethysmography were examined in conjunction with continuous video-EEG behavioural recordings in lesioned animals and sham-operated controls. The KD resulted in a peripheral ketosis observed both in the blood and urine. The KD led to a robust reduction in the frequency of spasms observed, with approximately a 1.5-fold increase in the rate of survival. Intriguingly, the KD resulted in an intracerebral acidosis as measured with P MRS. In addition, the respiratory profile of the lesioned rats on the KD was significantly altered with slower, deeper and longer breathing, resulting in decreased levels of expired CO. Sodium bicarbonate supplementation, acting as a pH buffer, partially reversed the KD's protective effects on spasm frequency. There were no differences in the mitochondrial respiratory profiles in the liver and brain frontal cortex measured between the groups, supporting the notion that the effects of the KD on breathing are not entirely due to changes in intermediary metabolism. Together, our results indicate that the KD produces its anticonvulsant effects through changes in respiration leading to intracerebral acidosis. These findings provide a novel understanding of the mechanisms underlying the anti-seizure effects of the KD in IS. Further research is required to determine whether the effects of the KD on breathing and intracerebral acid-base balance are seen in other paediatric models of epilepsy.
婴儿痉挛（IS）综合征是一种灾难性的婴儿期癫痫性脑病，通常对目前的抗癫痫治疗无效。生酮饮食（KD）已成为治疗药物难治性癫痫患者的一种替代疗法，不过KD对IS的前瞻性有效性及作用机制在很大程度上仍未得到探索。我们在难治性IS的啮齿动物模型中研究了KD的疗效及其作用机制。采用三重打击范式诱导痉挛，然后人工饲养动物，并使其食用KD（脂肪：碳水化合物+蛋白质比例为4:1）或对照乳类饮食（CM；比例为1.7:1）。在损伤动物和假手术对照中，结合连续视频脑电图行为记录检查磷磁共振波谱（P MRS）和头出式体积描记法。KD导致血液和尿液中出现外周酮症。KD使观察到的痉挛频率大幅降低，并使存活率提高了约1.5倍。有趣的是，用P MRS测量发现KD导致脑内酸中毒。此外，食用KD的损伤大鼠的呼吸模式明显改变，呼吸变慢、变深且变长，导致呼出的CO水平降低。作为pH缓冲剂的碳酸氢钠补充剂部分逆转了KD对痉挛频率的保护作用。两组之间测量的肝脏和脑额叶皮质中的线粒体呼吸模式没有差异，这支持了KD对呼吸的影响并非完全归因于中间代谢变化的观点。总之，我们的结果表明，KD通过导致脑内酸中毒的呼吸变化产生抗惊厥作用。这些发现为KD对IS抗癫痫作用的潜在机制提供了新的认识。还需要进一步研究以确定KD对呼吸和脑内酸碱平衡的影响是否在其他小儿癫痫模型中也能观察到。
