Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo)

Valproic acid (VPA), a known histone deacetylase inhibitor, has been used as an anticonvulsant in dogs. VPA also has anti-inflammatory properties, but there are no reports on the immunomodulatory effects of VPA in canine endotoxemia. In the present study, we demonstrate that the use of VPA significantly reduces the production of early-phase pro-inflammatory cytokines (TNF-α, IL-6) caused by lipopolysaccharide (LPS) stimulation both in vitro and in vivo.For the in vitro study, VPA was evaluated for 24 h on LPS (100 ng/ml)-treated canine peripheral blood mononuclear cells (PBMCs) which isolated from 5 healthy Beagle dogs. VPA significantly decreased the mRNA expression of TNF-α and IL-6 in a dose-dependent manner (p < 0.05 for IL-6; p < 0.01 for TNF-α).Fourteen adult Beagles were studied for in vivo study; nine dogs received a low dose of LPS (10 μg/kg/h) via continuous IV infusion for 12 h to induce endotoxemia whereas 5 dogs received normal saline as controls. Four out of 9 endotoxemic dogs were administered VPA (50 mg/kg, IV) at 1 h and 12 h along with the LPS infusion. Three hours after the first administration of VPA, IL-6 mRNA expressions in PBMCs significantly decreased (p = 0.033 vs. LPS group). VPA also significantly decreased the circulating TNF-α (p = 0.044 vs. LPS group at 3 h) and IL-6 protein at 3 h (p = 0.034 vs. LPS group) and 6 h (p = 0.026 vs. LPS group) post-treatment. Our study suggests that VPA attenuates the expression of pro-inflammatory cytokines in a canine endotoxemia model in vitro and in vivo. We speculate that valproic acid may be useful for reducing inflammatory cytokine levels in dogs with sepsis.