title: Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage.
abstract: BACKGROUND
  We have previously shown that addition of valproic acid (VPA; a histone deacetylase inhibitor) to hetastarch (Hextend [HEX]) resuscitation significantly decreases lesion size in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). However, the precise mechanisms have not been well defined. As VPA is a transcriptional modulator, the aim of this study was to investigate its effect on brain gene expression profiles.
  
  
  METHODS
  Swine were subjected to controlled TBI and HS (40% blood volume), kept in shock for 2 hours, and resuscitated with HEX or HEX + VPA (n = 5 per group). Following 6 hours of observation, brain RNA was isolated, and gene expression profiles were measured using a Porcine Gene ST 1.1 microarray (Affymetrix, Santa Clara, CA). Pathway analysis was done using network analysis tools Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis. Real-time polymerase chain reaction was used to verify the key microarray findings.
  
  
  RESULTS
  A total of 1,668 probe sets mapping to 370 known genes were differentially expressed between the HEX and HEX + VPA groups. Expression of apoptotic genes differed between groups, and biologic function analysis predicted a significant downregulation of apoptosis (p = 1.29 × 10), cell death (p = 8.46 × 10), and necrosis (p = 9.07 × 10). Pathway analysis indicated a significant modulation of pathways involved in cell signaling, dendritic cell response, and the complement system.
  
  
  CONCLUSIONS
  This is the first high-throughput analysis of cerebral gene profiling following TBI + HS. It shows that treatment with VPA significantly alters early transcription of pathways related to cell survival, which may explain its neuroprotective effects.
authors: From the Department of Surgery (S.E.D., T.B., B.L., G.J., Y.L., H.B.A.), University of Michigan Hospital, Ann Arbor, Michigan; Department of Anesthesiology (S.E.D.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Department of Surgery (M.S.), Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; Department of Surgery (M.S.), Copenhagen University Hospital, Hillerød, Denmark; and Biomedical Research Core Facilities (C.N.J.), DNA Sequencing Core Lab, University of Michigan, Ann Arbor, Michigan.
authors: Simone E
authors: SE
authors: Dekker
authors: Ted
authors: T
authors: Bambakidis
authors: Martin
authors: M
authors: Sillesen
authors: Baoling
authors: B
authors: Liu
authors: Craig N
authors: CN
authors: Johnson
authors: Guang
authors: G
authors: Jin
authors: Yongqing
authors: Y
authors: Li
authors: Hasan B
authors: HB
authors: Alam
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006895:Hydroxyethyl Starch Derivatives / Q000627:therapeutic use; D010952:Plasma Substitutes / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism; D013552:Swine; D059467:Transcriptome / Q000187:drug effects*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006895:Hydroxyethyl Starch Derivatives; D010952:Plasma Substitutes; D014635:Valproic Acid