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

• Published in: Journal of neurotrauma Vol. 33; no. 16; pp. 1514 - 1521
• Main Authors: Bambakidis, Ted, Dekker, Simone E, Sillesen, Martin, Liu, Baoling, Johnson, Craig N, Jin, Guang, de Vries, Helga E, Li, Yongqing, Alam, Hasan B
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 15.08.2016
• Subjects: Acids; Animals; Brain - drug effects; Brain - metabolism; Brain Injuries, Traumatic - drug therapy; Brain Injuries, Traumatic - metabolism; Cytokines - drug effects; Cytokines - metabolism; Disease Models, Animal; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Female; Hemorrhage; Hydroxyethyl Starch Derivatives - administration & dosage; Hydroxyethyl Starch Derivatives - pharmacology; Inflammatory diseases; Plasma Substitutes - administration & dosage; Plasma Substitutes - pharmacology; Resuscitation; Shock, Hemorrhagic - drug therapy; Shock, Hemorrhagic - metabolism; Swine; Transcriptome - drug effects; Traumatic brain injury; Valproic Acid - administration & dosage; Valproic Acid - pharmacology; in vivo studies; traumatic brain injury; genomics; inflammation; therapeutic approaches for the treatment of central nervous system injury
• ISSN: 0897-7151; 1557-9042
• DOI: 10.1089/neu.2015.4163

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.