title: mTOR inhibition by rapamycin protects against deltamethrin-induced apoptosis in PC12 Cells.
abstract: The autophagy pathway can be induced and upregulated in response to intracellular reactive oxygen species (ROS). In this study, we explored a novel pharmacotherapeutic approach involving the regulation of autophagy to prevent deltamethrin (DLM) neurotoxicity. We found that DLM-induced apoptosis in PC12 cells, as demonstrated by the activation of caspase-3 and -9 and by nuclear condensation. DLM treatment significantly decreased dopamine (DA) levels in PC12 cells. In addition, we observed that cells treated with DLM underwent autophagic cell death, by monitoring the expression of LC3-II, p62, and Beclin-1. Exposure of PC12 cells to DLM led to the production of ROS. Treatment with N-acetyl cysteine (NAC) effectively blocked both apoptosis and autophagy. In addition, mitogen-activated protein kinase (MAPK) inhibitors attenuated apoptosis as well as autophagic cell death. We also investigated the modulation of DLM-induced apoptosis in response to autophagy regulation. Pretreatment with the autophagy inducer, rapamycin, significantly enhanced the viability of DLM-exposed cells, and this enhancement of cell viability was partially due to alleviation of DLM-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), significantly increased DLM toxicity in these cells. Our results suggest that DLM-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against DLM-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 109-121, 2017.
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Korea.|Hanyang Biomedical Research Institute, Seoul, Republic of Korea.|Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Yun Sun
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Korea.|Hanyang Biomedical Research Institute, Seoul, Republic of Korea.|Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Korea.|Hanyang Biomedical Research Institute, Seoul, Republic of Korea.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Ko
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Korea.|Hanyang Biomedical Research Institute, Seoul, Republic of Korea.
authors.forename: In Chul
authors.initials: IC
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Korea.|Hanyang Biomedical Research Institute, Seoul, Republic of Korea.|Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Koh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D009570:Nitriles / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016716:PC12 Cells; D011722:Pyrethrins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; D017382:Reactive Oxygen Species; C017180:decamethrin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D004298:Dopamine; D020123:Sirolimus
keywords: apoptosis; autophagy; deltamethrin; neuroprotection; rapamycin