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Journal of Trauma and Acute Care Surgery:
doi: 10.1097/TA.0000000000000345
WTA 2014 Plenary Papers

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

Dekker, Simone E.; Bambakidis, Ted MSc; Sillesen, Martin MD; Liu, Baoling MD; Johnson, Craig N. PSM; Jin, Guang MD, PhD; Li, Yongqing MD, PhD; Alam, Hasan B. MD

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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 × 10−12), 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.

© 2014 Lippincott Williams & Wilkins, Inc.

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