Alterations in the human proteome following administration of valproic acid.

Background: High doses of the histone deacetylase inhibitor Valproic Acid (VPA, 150-400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting an FDA approved phase 1, double blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. Methods: Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over one hour) at baseline, 4, and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis(R) and Panther Gene Ontology. Results: A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1716 +/- 459. There were a total of 140 unique differentially expressed proteins (p

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