Department of Pharmacy, Pharmaceutical Sciences Research Center, Children's Hospital of Nanjing Medical University, Nanjing, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Epilepsia Open. 2023 Jun;8(2):466-478. doi: 10.1002/epi4.12712. Epub 2023 Mar 1.
The drug-refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy.
This single-center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. Ninety plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non-responders with VPA polytherapy (NR group) were collected. Non-targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value >1, fold change >1.2 or <0.8, and p-value <0.05 were regarded as statistically different substances.
A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well-established partial least squares-discriminant analysis (PLS-DA) revealed a good separation of the RE from the NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine laboratory tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L-thyroxine, but with an increased level of glucose and 2-oxoglutarate. The top two enriched metabolic pathways involved in the DRE condition were biosynthesis of unsaturated FAs and linoleic acid metabolism.
The results of this study suggested an association between metabolism of FAs and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high-priority strategies for DRE management.
儿童药物难治性癫痫（DRE）较为常见，但潜在机制仍难以捉摸。我们研究了脂肪酸（FAs）和脂质是否与丙戊酸（VPA）治疗耐药有关。
本单中心回顾性队列研究使用 2019 年 5 月至 2019 年 12 月南京医科大学附属儿童医院收集的儿科患者数据进行。收集 53 例接受 VPA 单药治疗的患者（RE 组）和 37 例接受 VPA 多药治疗的患者（NR 组）的 90 份血浆样本。对这些血浆样本进行非靶向代谢组学和脂质组学分析，以比较两组之间小代谢物和脂质的潜在差异。通过投影值>1、倍数变化>1.2 或<0.8 且 p 值<0.05 的变量重要性阈值的血浆代谢物和脂质被视为具有统计学差异的物质。
共鉴定出 204 种小代谢物和 433 种脂质，包括 16 种不同的脂质亚类。经过验证的偏最小二乘判别分析（PLS-DA）显示，RE 组与 NR 组之间有很好的分离。NR 组的 FAs 和甘油磷脂状态显著降低，但其三酰甘油（TG）水平显著升高。常规实验室检查中 TG 水平的趋势与脂质组学分析一致。同时，NR 组的病例表现为柠檬酸和 L-甲状腺素水平降低，葡萄糖和 2-氧戊二酸水平升高。涉及 DRE 状态的前两个富集代谢途径是不饱和 FAs 的生物合成和亚油酸代谢。
这项研究的结果表明，FAs 代谢与医学上难治性癫痫之间存在关联。这些新发现可能提出了与能量代谢有关的潜在机制。因此，生酮饮食和 FAs 补充可能是 DRE 管理的优先策略。
