Resuscitation with Valproic Acid Alters Inflammatory Genes in a Porcine Model of Combined Traumatic Brain Injury and Hemorrhagic Shock

Abstract

Traumatic brain injury and hemorrhagic shock (TBI+HS) elicit a complex inflammatory response that contributes to secondary brain injury. There is currently no proven pharmacologic treatment for TBI+HS, but modulation of the epigenome has been shown to be a promising strategy. The aim of this study was to investigate whether valproic acid (VPA), a histone deacetylase inhibitor, modulates the expression of cerebral inflammatory gene profiles in a large animal model of TBI+HS. Ten Yorkshire swine were subjected to computer-controlled TBI+HS (40% blood volume). After 2 h of shock, animals were resuscitated with Hextend (HEX) or HEX+VPA (300 mg/kg, n = 5/group). Six hours after resuscitation, brains were harvested, RNA was isolated, and gene expression profiles were measured using a porcine microarray. Ingenuity Pathway Analysis® (IPA), gene ontology (GO), Parametric Gene Set Enrichment Analysis (PGSEA), and DAVID (Database for Annotation, Visualization, and Integrated Discovery) were used for pathway analysis. Key microarray findings were verified using real-time polymerase chain reaction (PCR). IPA analysis revealed that VPA significantly down-regulated the complement system (p< 0.001), natural killer cell communication (p < 0.001), and dendritic cell maturation (p < 0.001). DAVID analysis indicated that a cluster of inflammatory pathways held the highest rank and gene enrichment score. Real-time PCR data confirmed that VPA significantly down-expressed genes that ultimately regulate nuclear factor-kB (NF-kB)-mediated production of cytokines, such as TYROBP, TREM2, CCR1, and IL-1β. This high-throughput analysis of cerebral gene expression shows that addition of VPA to the resuscitation protocol significantly modulates the expression of inflammatory pathways in a clinically realistic model of TBI+HS.

Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury

“…A growing body of literature suggests that valproic acid may alter gene expression and protein functions following TBI (Dekker, 2014b; Halaweish, 2015b; Bambakidis 2016). Valproic acid has been in clinical use as a mood stabilizing and anti-epileptic and drug since the 1970s.…”

“…The anti-inflammatory properties of valproic acid treatment have been described previously in models of sepsis, hemorrhage, and TBI (Shang, 2010; Jin, 2012a; Liu, 2014). In addition, Bambakidis et al (2016) showed that valproic acid modulates genes related to inflammation, cell signaling, cell adhesion, and endothelial growth. Dash et al (2010) furthermore showed that valproic acid treatment significantly decreased Evans Blue dye extravasation in a TBI rat model, indicating that valproic acid might restore BBB function following trauma.…”

The ‘Omics’ of Epigenetic Modulation by Valproic Acid Treatment in Traumatic Brain Injury—What We Know and What the Future Holds

“…VPA administration also significantly downregulates genetic pathways involved in inflammatory responses . Administration of a single dose of VPA inhibited the complement system and natural killer intercellular communication, dendritic cell maturation, T cell, and B cell signaling and pattern recognition receptors in recognition of bacteria and viruses.…”

“…VPA administration alters multiple genomic changes following TBI. Using microarray technique, we studied the effects of VPA on brain gene expression in swine subjected to TBI (controlled cortical impact) and hemorrhagic shock (HS) . VPA was found to affect the expression of 370 well‐known genes following TBI and HS.…”

Trauma care: Finding a better way

“…Treatment with fresh frozen plasma (FFP) has also been shown to be very effective, both as a monotherapy [17] and in combination with VPA—resulting in a synergistic effect [18]. VPA treatment up-regulates expression of beneficial genes in the injured brain [19,20], modulates posttraumatic brain metabolism [21], and improves long-term neurological recovery and healing [22] in clinically relevant models of TBI combined with HS.…”