Tetrachlorobenzoquinone exhibits neurotoxicity by inducing inflammatory responses through ROS-mediated IKK/IκB/NF-κB signaling

Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-kappa B) signaling. The activation of NF-kappa B was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) alpha/beta, p-IKK alpha/beta, an inhibitor of NF-kappa B (I kappa B) alpha, p-I kappa B alpha, NF-kappa B (p65) and p-p65. The translocation of NF-kappa B was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-kappa B inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-kappa B signaling. Moreover, antioxidants, i.e., N-acetyl-L-cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-kappa B, which implied that ROS serve as the upstream molecule of NF-kappa B signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IKB/NF-kappa B pathway in PC12 cells. (C) 2015 Elsevier B.V. All rights reserved.