From the Department of Surgery (U.F.B., I.S.D., A.M.W., V.C.N., B.E.B., A.S., R.L.O., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (U.F.B.), Washington University, St. Louis, Missouri; Department of Surgery (H.B.A.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Computational Medicine and Bioinformatics (A.K.), and Michigan Regional Comprehensive Metabolomics Resource Core (M.K.), University of Michigan Health System, Ann Arbor, Michigan.
J Trauma Acute Care Surg. 2021 Mar 1;90(3):507-514. doi: 10.1097/TA.0000000000003026.
Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.
We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography-mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada).
In untargeted reversed-phase liquid chromatography-mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001).
Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.
创伤性脑损伤（TBI）是创伤相关发病率和死亡率的主要原因。已证明丙戊酸（VPA）可在 TBI 发生后的最初几个小时内减轻脑损伤的大小和肿胀。由于受伤的神经元对代谢变化敏感，我们假设 VPA 治疗会改变病变周围脑组织的代谢谱，从而创造一个神经保护的环境。
我们使猪遭受联合 TBI（12-mm 皮质撞击）和失血性休克（40%血容量损失和 2 小时低血压），并将它们随机分为两组（每组 n = 5）：（1）生理盐水（NS；3×出血体积）和（2）NS-VPA（NS，3×出血体积；VPA，150mg/kg）。6 小时后，采集大脑，并使用 100mg 病变周围组织进行代谢产物提取。使用反相液相色谱-质谱法在正离子和负离子模式下分析样品，并使用 MetaboAnalyst 软件（加拿大魁北克省麦吉尔大学）分析数据。
在非靶向反相液相色谱-质谱分析中，我们分别在正离子和负离子模式下检测到 3750 和 1955 种代谢产物。正离子模式下没有明显不同的代谢产物；然而，负离子模式下有 167 种代谢产物特征有显著差异（p<0.05），其中包括 VPA 衍生物。途径分析表明，治疗组中的几个途径受到影响，包括不饱和脂肪酸的生物合成（p=0.001）。糖酵解/三羧酸（TCA）循环的靶向氨基酸分析显示，VPA 治疗显著降低了兴奋性氨基酸丝氨酸的水平（p=0.001）。
丙戊酸可以以其代谢产物的形式在病变周围组织中被检测到。它还可在 TBI 发生后的最初几个小时内引起大脑的代谢变化，从而创造一个神经保护的环境。
