Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

Simone E. Dekker, Ted Bambakidis, Martin Sillesen, Baoling Liu, Craig N. Johnson, Guang Jin, Yongqing Li, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 RNAwas 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 × 10-12), cell death (p = 8.46 × 10-12), and necrosis (p = 9.07 × 10-11). Pathway analysis indicated a significant modulation of pathways involved in cell signaling, dendritic cell response, and the complement system.

Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)906-912
Number of pages7
JournalJournal of Trauma and Acute Care Surgery
Volume77
Issue number6
DOIs
StatePublished - Dec 11 2014
Externally publishedYes

Keywords

  • Apoptosis
  • Brain
  • Genes
  • Hemorrhage
  • Injury
  • Pigs

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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