Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

Umar F Bhatti Alla Karnovsky Isabel S Dennahy Maureen Kachman Aaron M Williams Vahagn C Nikolian Ben E Biesterveld Ali Siddiqui Rachel L O'Connell Baoling Liu Yongqing Li Hasan B Alam

J Trauma Acute Care Surg

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.

Published: March 2021

Traumatic brain injury (TBI) is a major cause of serious health issues, and valproic acid (VPA) has shown potential in reducing brain damage shortly after TBI by altering metabolic profiles in the affected areas.
In a study involving swine, researchers compared the effects of normal saline versus saline with VPA treatment on metabolic changes in the brain following TBI and hemorrhagic shock.
Results showed significant metabolic differences in the VPA-treated group, particularly a decrease in the excitotoxic amino acid serine and alterations in pathways related to fatty acid biosynthesis, indicating VPA's potential neuroprotective effects.

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.

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http://dx.doi.org/10.1097/TA.0000000000003026	DOI Listing

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