Hanin Aurélie, Chollet Céline, Demeret Sophie, Di Meglio Lucas, Castelli Florence, Navarro Vincent
Comprehensive Epilepsy Center, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié-Salpêtrière, Paris, France.
Epilepsia. 2024 Apr;65(4):929-943. doi: 10.1111/epi.17899. Epub 2024 Feb 10.
OBJECTIVE: Status epilepticus (SE) is a life-threatening prolonged epileptic seizure that affects ~40 per 100 000 people yearly worldwide. The persistence of seizures may lead to excitotoxic processes, neuronal loss, and neuroinflammation, resulting in long-term neurocognitive and functional disabilities. A better understanding of the pathophysiological mechanisms underlying SE consequences is crucial for improving SE management and preventing secondary neuronal injury. METHODS: We conducted a comprehensive untargeted metabolomic analysis, using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS), on plasma and cerebrospinal fluid (CSF) samples from 78 adult patients with SE and 107 control patients without SE, including 29 with CSF for both groups. The metabolomic fingerprints were compared between patients with SE and controls. Metabolites with differences in relative abundances that could not be attributed to treatment or nutrition provided in the intensive care unit were isolated. Enrichment analysis was performed on these metabolites to identify the most affected pathways. RESULTS: We identified 76 metabolites in the plasma and 37 in the CSF that exhibited differential expression in patients with SE compared to controls. The enrichment analysis revealed that metabolic dysregulations in patients with SE affected primarily amino acid metabolism (including glutamate, alanine, tryptophan, glycine, and serine metabolism), pyrimidine metabolism, and lipid homeostasis. Specifically, patients with SE had elevated levels of pyruvate, quinolinic acid, and keto butyric acid levels, along with lower levels of arginine, N-acetylaspartylglutamate (NAAG), tryptophan, uracil, and uridine. The tryptophan kynurenine pathway was identified as the most significantly altered in SE, resulting in the overproduction of quinolinic acid, an N-methyl-d-aspartate (NMDA) receptor agonist with pro-inflammatory properties. SIGNIFICANCE: This study has identified several pathways that may play pivotal roles in SE consequences, such as the tryptophan kynurenine pathway. These findings offer novel perspectives for the development of neuroprotective therapeutics.
目的：癫痫持续状态（SE）是一种危及生命的长时间癫痫发作，全球每年每10万人中约有40人受其影响。癫痫发作的持续可能导致兴奋性毒性过程、神经元丧失和神经炎症，从而导致长期的神经认知和功能障碍。更好地理解SE后果背后的病理生理机制对于改善SE的管理和预防继发性神经元损伤至关重要。 方法：我们使用液相色谱与高分辨率质谱联用（LC-HRMS），对78例成年SE患者和107例无SE的对照患者的血浆和脑脊液（CSF）样本进行了全面的非靶向代谢组学分析，其中两组均有29例提供了脑脊液样本。比较了SE患者和对照患者的代谢组指纹图谱。分离出相对丰度存在差异且不能归因于重症监护病房提供的治疗或营养的代谢物。对这些代谢物进行富集分析，以确定受影响最严重的途径。 结果：我们在血浆中鉴定出76种代谢物，在脑脊液中鉴定出37种代谢物，与对照组相比，这些代谢物在SE患者中表现出差异表达。富集分析表明，SE患者的代谢失调主要影响氨基酸代谢（包括谷氨酸、丙氨酸、色氨酸、甘氨酸和丝氨酸代谢）、嘧啶代谢和脂质稳态。具体而言，SE患者的丙酮酸、喹啉酸和酮丁酸水平升高，而精氨酸、N-乙酰天冬氨酰谷氨酸（NAAG）、色氨酸、尿嘧啶和尿苷水平降低。色氨酸犬尿氨酸途径被确定为SE中变化最显著的途径，导致具有促炎特性的N-甲基-D-天冬氨酸（NMDA）受体激动剂喹啉酸的过量产生。 意义：本研究确定了几条可能在SE后果中起关键作用的途径，如色氨酸犬尿氨酸途径。这些发现为神经保护疗法的开发提供了新的视角。
Amino Acids. 2024-12-13
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