Valproic Acid Increases Susceptibility to Endotoxin Shock Through Enhanced Release of High-Mobility Group Box 1

Abstract

High-mobility group box 1 (HMGB1) is a nuclear factor and a secreted protein. During inflammation, HMGB1 is secreted into the extracellular space where it can interact with the receptor for advanced glycation end products and trigger proinflammatory signals. Extracellular HMGB1 plays a critical role in several inflammatory diseases such as sepsis and rheumatoid arthritis. Valproic acid (VPA) is one of the most frequently prescribed antiepileptic drugs. The present study was undertaken to investigate the effect of VPA on secretion of HMGB1 in systemic inflammatory responses induced by lipopolysaccharide. Pretreatment with VPA increased the susceptibility of mice to lipopolysaccharide in endotoxemia. Valproic acid induced HMGB1 release and nuclear factor κB activation in RAW-blue cells. Valproic acid promoted the phosphorylation of ERK1/2 but not that of p38 or JNK. The MEK1/2 inhibitor PD98059 also suppressed HMGB1 release and activation of nuclear factor κB induced by VPA. Valproic acid induced expression of γ-aminobutyric acid receptors in macrophages, and picrotoxin, a γ-aminobutyric acid A receptor antagonist, inhibited the VPA-activated phosphorylation of ERK and VPA-induced HMGB1 release. These results suggest that VPA may exacerbate innate immune responses to endotoxin through enhanced release of HMGB1.

Combined Transcriptomics and Chemical-Genetics Reveal Molecular Mode of Action of Valproic acid, an Anticancer Molecule using Budding Yeast Model

“…4 ). The resistance of IXR1 null mutant which encodes an HMG domain-containing protein to VA is in accordance with an earlier study that shows VA exacerbate innate immune responses to endotoxin by enhancing the release of High-mobility group box-1 (HMGB1) 47 . Altogether, our results demonstrated that VA mediates its toxicity through alteration of genomic stability, redox and lipid homeostasis, ER and mitochondrial functions.…”

Development of a novel neuroprotective strategy: Combined treatment with hypothermia and valproic acid improves survival in hypoxic hippocampal cells

“…36,37 On the other hand, HMGB1 has also been reported to be a substrate for histone acetylase, and HDAC inhibitors can increase the release and relocation of HMGB1 from the nucleus to the cytoplasm. 38–40 In this study, we detected an increase in HMGB1 in the VPA treated group (Fig 8). It could be a “side effect” of VPA, although the VPA treatment exhibited an overall neuroprotective effect.…”

Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

“…In contrast, VPA can exacerbate the RAW264.7 macrophage response to LPS by increasing the release of the nuclear factor HMGB1, which associates with the promotion of inflammatory processes. This effect is mediated by an increase in the expression of the GABA receptor, leading to phosphorylation of the transcription factor ERK1/2, without promoting either p38 or c-JUN phosphorylation [62].…”