Pharmacologic Modulation of Brain Metabolism by Valproic Acid can Induce a Neuroprotective Environment.

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. As 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): (i) normal saline (NS; 3×hemorrhage volume); (ii) NS + VPA (NS; 3×hemorrhage volume, VPA; 150mg/kg). After six hours, brains were harvested and 100mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using Reversed-Phase Liquid Chromatography-Mass Spectrometry (RPLC-MS) in positive and negative ion modes and data analyzed using Metaboanalyst software. RESULTS In untargeted RPLC-MS analysis, we detected 3750 and 1955 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-values < 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/TCA cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p=0.001). CONCLUSION VPA 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. LEVEL OF EVIDENCE not applicable (pre-clinical study).