Abstract：
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
目的：癫痫持续状态（SE）是一种威胁生命的长期癫痫发作，每年影响全球每10万人中约40人。癫痫发作的持续可能导致兴奋性毒性过程，神经元丢失，和神经炎症，导致长期的神经认知和功能障碍。更好地了解SE后果的病理生理机制对于改善SE管理和预防继发性神经元损伤至关重要。
方法：我们进行了全面的非目标代谢组学分析，使用液相色谱与高分辨率质谱联用（LC-HRMS），来自78例成人SE患者和107例无SE对照患者的血浆和脑脊液（CSF）样本，包括两组的29个CSF。比较SE患者和对照组之间的代谢组学指纹。分离出相对丰度差异的代谢物，这些代谢物不能归因于重症监护病房提供的治疗或营养。对这些代谢物进行富集分析以鉴定受影响最大的途径。
结果：我们确定了血浆中的76种代谢物和CSF中的37种代谢物，这些代谢物在SE患者中与对照组相比表现出差异表达。富集分析显示，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。具体来说,SE患者丙酮酸水平升高，喹啉酸,和酮丁酸水平，随着精氨酸水平的降低，N-乙酰天冬氨酰谷氨酸(NAAG),色氨酸,尿嘧啶,和尿苷。色氨酸犬尿氨酸途径被认为是SE中最显著改变的途径，导致喹啉酸的过量生产，一种具有促炎特性的N-甲基-d-天冬氨酸（NMDA）受体激动剂。
结论：这项研究确定了几种可能在SE后果中起关键作用的途径，例如色氨酸犬尿氨酸途径。这些发现为神经保护疗法的发展提供了新的观点。
方法：我们进行了全面的非目标代谢组学分析，使用液相色谱与高分辨率质谱联用（LC-HRMS），来自78例成人SE患者和107例无SE对照患者的血浆和脑脊液（CSF）样本，包括两组的29个CSF。比较SE患者和对照组之间的代谢组学指纹。分离出相对丰度差异的代谢物，这些代谢物不能归因于重症监护病房提供的治疗或营养。对这些代谢物进行富集分析以鉴定受影响最大的途径。
结果：我们确定了血浆中的76种代谢物和CSF中的37种代谢物，这些代谢物在SE患者中与对照组相比表现出差异表达。富集分析显示，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。具体来说,SE患者丙酮酸水平升高，喹啉酸,和酮丁酸水平，随着精氨酸水平的降低，N-乙酰天冬氨酰谷氨酸(NAAG),色氨酸,尿嘧啶,和尿苷。色氨酸犬尿氨酸途径被认为是SE中最显著改变的途径，导致喹啉酸的过量生产，一种具有促炎特性的N-甲基-d-天冬氨酸（NMDA）受体激动剂。
结论：这项研究确定了几种可能在SE后果中起关键作用的途径，例如色氨酸犬尿氨酸途径。这些发现为神经保护疗法的发展提供了新的观点。
