Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 278, Issue 2, Pages 159-171Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2014.04.021
Keywords
Chlorpyrifos; Reactive oxidative species; NF-kappa B; COX-2; Rosiglitazone
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Funding
- Korea Science and Engineering Foundation through the Medical Research Center at Hanyang University College of Medicine, Republic of Korea [NRF-2008-0062287]
- National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [NRF-2010-0024012]
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Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-kappa B) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, against CPF-induced neuronal cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-alpha. CPF also induced nuclear translocation of NF-kappa B and inhibitors of NF-kappa B abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-kappa B-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-kappa B. Crown Copyright (C) 2014 Published by Elsevier Inc. All rights reserved.
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