TY - JOUR
T1 - Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment
AU - Bhatti, Umar F.
AU - Karnovsky, Alla
AU - Dennahy, Isabel S.
AU - Kachman, Maureen
AU - Williams, Aaron M.
AU - Nikolian, Vahagn C.
AU - Biesterveld, Ben E.
AU - Siddiqui, Ali
AU - O’Connell, Rachel L.
AU - Liu, Baoling
AU - Li, Yongqing
AU - Alam, Hasan B.
N1 - Funding Information:
The authors declare no conflicts of interest. This work was supported by NIH RO1 GM084127 (H.B.A.) and Michigan Regional Comprehensive Metabolomics Resource Core, Small Grant (I.S.D.).
Publisher Copyright:
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
AB - OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
KW - Histone deacetylation
KW - metabolomics
KW - swine
KW - traumatic brain injury
KW - valproic acid
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U2 - 10.1097/TA.0000000000003026
DO - 10.1097/TA.0000000000003026
M3 - Article
C2 - 33196629
AN - SCOPUS:85102214657
SN - 2163-0755
VL - 90
SP - 507
EP - 514
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 3
ER -