title: The Neuroprotective Effect of Erythropoietin on Rotenone-Induced Neurotoxicity in SH-SY5Y Cells Through the Induction of Autophagy.
abstract: Currently, the autophagy pathway is thought to be important for the pathogenesis of Parkinson's disease (PD), and the modulation of autophagy may be a novel strategy for the treatment of this disease. Erythropoietin (EPO) has been reported to have neuroprotective effects through anti-oxidative, anti-apoptotic, and anti-inflammatory mechanisms, and it has also been shown to modulate autophagy signaling in an oxygen toxicity model. Therefore, we investigated the effects of EPO on autophagy markers and evaluated its neuroprotective effect on rotenone-induced neurotoxicity. We adapted the rotenone-induced neurotoxicity model to SH-SY5Y cells as an in vitro model of PD. We measured cell viability using MTT and annexin V/propidium iodide assays and measured intracellular levels of reactive oxygen species. Immunofluorescence analysis was performed to measure the expression of LC3 and α-synuclein. Intracellular signaling proteins associated with autophagy were examined by immunoblot analysis. EPO mono-treatment increased the levels of mammalian target of rapamycin (mTOR)-independent/upstream autophagy markers, including Beclin-1, AMPK, and ULK-1. Rotenone treatment of SH-SY5Y cells reduced their viability, increased reactive oxygen species levels, and induced apoptosis and α-synuclein expression, and simultaneous exposure to EPO significantly reduced these effects. Rotenone enhanced mTOR expression and suppressed Beclin-1 expression, indicating suppression of the autophagy system. However, combined treatment with EPO restored Beclin-1 expression and decreased mTOR expression. EPO protects against rotenone-induced neurotoxicity in SH-SY5Y cells by enhancing autophagy-related signaling pathways. The experimental evidence for the EPO-induced neuroprotection against rotenone-induced dopaminergic neurotoxicity may significantly impact the development of future PD treatment strategies.
authors.affiliation: Department of Neurology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Bangdong-ri, Sacheon-myeon, Gangneung, Gangwon-do, 210-711, Republic of Korea. neveu@gnah.co.kr.|Biomedical Research Center, Gangneung Asan Hospital, Bangdong-ri, Sacheon-myeon, Gangneung, 210-711, Gangwon-do, Republic of Korea. neveu@gnah.co.kr.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Jang
authors.affiliation: Natural Products Research Center, Korea Institute of Science and Technology, 679 Saimdang-ro, Gangneung, 210-340, Republic of Korea.|Biomedical Research Center, Gangneung Asan Hospital, Bangdong-ri, Sacheon-myeon, Gangneung, 210-711, Gangwon-do, Republic of Korea.
authors.forename: Hee Ju
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Natural Products Research Center, Korea Institute of Science and Technology, 679 Saimdang-ro, Gangneung, 210-340, Republic of Korea.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Bangdong-ri, Sacheon-myeon, Gangneung, Gangwon-do, 210-711, Republic of Korea.
authors.forename: Kwang Deog
authors.initials: KD
authors.lastname: Jo
authors.affiliation: Department of Neurology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Bangdong-ri, Sacheon-myeon, Gangneung, Gangwon-do, 210-711, Republic of Korea.
authors.forename: Moon Kyu
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Natural Products Research Center, Korea Institute of Science and Technology, 679 Saimdang-ro, Gangneung, 210-340, Republic of Korea. hoyang@kist.re.kr.
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D012402:Rotenone; D004921:Erythropoietin
keywords: Autophagy; Erythropoietin; Neuroprotection; Parkinson’s disease