T. Bambakidis1, S. E. Dekker1, M. Sillesen1, B. Liu1, C. N. Johnson1, I. Halaweish1, Y. Li1, H. B. Alam1 1University Of Michigan,Surgery,Ann Arbor, MI, USA
Introduction: We have reported that valproic acid (VPA) can create a pro-survival gene expression profile in various models of lethal insults, and its administration can significantly decrease brain lesion size and surrounding inflammation, in a swine model of combined traumatic brain injury (TBI) + hemorrhagic shock (HS). It, however, remains unknown whether this neuroprotective effect is driven by alterations in the expression of cerebral inflammatory genes.
Methods: Computer-controlled TBI (cortical impact) and HS (40% blood volume) were induced in 10 Yorkshire swine. After two hours of shock, animals were randomly treated with either 6% hextend (HEX; 1x shed blood) or HEX+VPA (300mg/kg) (n=5/group). Six hours after resuscitation, brains were harvested, RNA isolated, and gene expression profiles measured using a Porcine Gene ST 1.1 microarray (Affymetrix, CA). Ingenuity Pathway Analysis® (IPA), Gene Ontology (GO), and Parametric Gene Set Enrichment Analysis (PGSEA) were used for pathway analysis. Key microarray findings were verified using real-time polymerase chain reaction (PCR).
Results: Of the 1753 genes modulated by VPA, significant alterations were noted in genes related to the inflammatory response. 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) (Figure). Real-time PCR data confirmed that VPA significantly decreased the expression of genes associated with inflammation, such as CCR1 (P=0.01), IL-1β (P=0.003), TREM2 (P=0.02), and TYROBP (P=0.05).
Conclusion: This is the first high-throughput analysis of cerebral gene expression profile following TBI+HS which reveals that VPA treatment significantly attenuates inflammatory pathways.
