Valproic acid accelerates skin wound healing in mice via its anti-inflammatory and apoptotic cell clearance-promoting effects

Objective: To investigate the effects of valproic acid (VPA) on skin wound healing in mice.

Methods: Full-thickness wounds were created in mice, and then VPA was applied. The wound areas were quantified daily. In the wounds, granulation tissue growth, epithelialization, collagen deposition, and the mRNA levels of inflammatory cytokines were measured; furthermore, apoptotic cells were labeled. In vitro, VPA was added to RAW 264.7 cells (macrophages) stimulated with lipopolysaccharide, and apoptotic Jurkat cells were cocultured with the VPA-pretreated macrophages. Then, phagocytosis was analyzed, and the mRNA levels of phagocytosis-associated molecules and inflammatory cytokines were measured in the macrophages.

Results: VPA application significantly accelerated wound closure, granulation tissue growth, collagen deposition, and epithelialization. In wounds, the levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β were decreased by VPA, whereas those of IL-10 and transforming growth factor-β1 were increased. Additionally, VPA reduced the number of apoptotic cells. In vitro, VPA inhibited the inflammatory activation of macrophages and promoted the phagocytosis of apoptotic cells by macrophages.

Conclusion: VPA accelerated skin wound healing, which could be partly attributable to its anti-inflammatory and apoptotic cell clearance-promoting effects, indicating that VPA could be a promising candidate for enhancing skin wound healing.

Wound healing; apoptosis; cytokine; inflammation; macrophage; phagocytosis; valproic acid.