2,4-Dihydroxyphenyl-benzo[<i>d</i>]thiazole (MHY553), a synthetic PPARα agonist, decreases age-associated inflammatory responses through PPARα activation and RS scavenging in the skin

Abstract

We previously reported that 2,4-dihydroxyphenyl-benzo[d]thiazole (MHY553) is a PPAR alpha agonist, which has been shown to inhibit tyrosinase activity in murine melanocyte and alleviate hepatic steatosis in aged rats. This study investigated the effects of MHY553 on the age-related occurrence of inflammatory responses via the molecular modulation of the nuclear factor-kappa B (NF-kappa B) signaling pathway in the skin of aged rats and skin fibroblast cells. Moreover, we investigated the antioxidant effect of MHY553 via in vitro assays of reactive oxygen species (ROS) and peroxynitrite (ONOO-) scavenging activities. We also scrutinized the ability of MHY553 as a PPAR alpha activator in aged rat skin and H2O2-induced Hs27 fibroblast cells. In vivo experiments were performed in young, aged, and MHY553-fed aged rats (3 mg or 5 mg.kg(-1).day(-1) for 4 weeks). MHY553 dose-dependently scavenged ROS and ONOO-. Furthermore, we found that MHY553 suppressed the NF-kappa B transcription factor and downregulated mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling. MHY553 also inhibited the expression of pro-inflammatory cytokines including COX-2, iNOS, IL-1 beta, and IL-6. Our findings indicate the MHY553 scavenges ROS/reactive nitrogen species and inhibits inflammatory cytokines through PPAR alpha activation in the skin. Thus, these results suggest that MHY553 may be of therapeutic interest for protecting skin from oxidative stress-induced damage and intrinsic aging.