Targeting Oxidative Stress, Transforming Growth Factor Beta-1, and the Mammalian Target of Rapamycin by Valproic Acid to Ameliorate Bleomycin-Induced Scleroderma

Abstract

Objective: To explore the possible ameliorative effect of valproic acid on the experimental model of skin fibrosis induced by bleomycin.Materials and Methods: Forty male BALB/c mice were divided into four equal groups as follows: control group, bleomycin group, bleomycin + Valproic acid group, and Valproic acid group. Mice were assessed for their body weight every 3 days throughout the whole study. Skin tissues were used to evaluate the oxidative stress parameters, transforming growth factor beta 1 (TGF-β1), tumor necrosis factor alpha, interleukin 15, and mammalian target of rapamycin (mTOR). Skin fibrosis was evaluated by measuring dermal thickness and staining the skin tissues with Masson trichrome stain. Furthermore, the skin tissues were immunostained with alpha smooth muscle actin (α-SMA).Results: Administration of Valproic acid to bleomycin-treated mice resulted in the restoration of the body weight with significant decrease in the dermal thickness, amelioration of oxidative stress, suppression of TGF-β1 and mTOR expression, and significant reduction of the percentage of α-SMA immunostaining and the proinflammatory cytokine levels compared to mice treated with bleomycin alone.Conclusion: Valproic acid has an antifibrotic effect on skin fibrosis which may represent a beneficial therapeutic modality for the management of scleroderma.

Keywords: Bleomycin; mice; scleroderma; transforming growth factor beta 1; Valproic acid