title: Atorvastatin Protects NSC-34 Motor Neurons Against Oxidative Stress by Activating PI3K, ERK and Free Radical Scavenging.
abstract: Although statins, or hydroxymethylglutaryl coenzyme A (HMG-Co A) reductase inhibitors, are generally used to decrease levels of circulating cholesterol, they have also been reported to have neuroprotective effects through various mechanisms. However, recent results have indicated that they may be harmful in patients with amyotrophic lateral sclerosis (ALS). In this study, we investigate whether atorvastatin protects motor neuron-like cells (NSC-34D) from oxidative stress. To evaluate the effects of atorvastatin or hydrogen peroxide or both on NSC-34D cells, the cells were treated with various combinations of these agents. To evaluate the viability of the cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and trypan blue staining were performed. Levels of free radicals and intracellular signaling proteins were evaluated using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. Atorvastatin protected NSC-34D cells against oxidative stress in a concentration-dependent manner. This neuroprotective effect of atorvastatin was blocked by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor and by FR180204, a selective extracellular signal-related kinase (ERK) inhibitor. Atorvastatin treatment increased the expression levels of p85αPI3K, phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, phosphorylated ERK, and Bcl-2, which are proteins related to survival. Furthermore, atorvastatin decreased the levels of cytosolic cytochrome C, Bax, cleaved caspase-9, and cleaved caspase-3, which are associated with death in oxidative stress-injured NSC-34D cells. We conclude that atorvastatin has a protective effect against oxidative stress in motor neurons by activating the PI3K and ERK pathways as well as by scavenging free radicals. These findings indicate that statins could help protect motor neurons from oxidative stress.
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, South Korea.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Choi
authors.affiliation: Department of Neurology, Bundang Jesaeng Hospital, Gwangju, Gyeonggi Province, South Korea.
authors.forename: Hyun-Jeung
authors.initials: HJ
authors.lastname: Yu
authors.affiliation: Department of Neurology, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, South Korea.
authors.forename: Jinse
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, South Korea.
authors.forename: Hojin
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, South Korea.
authors.forename: Kyu-Yong
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Radiology, College of Medicine, Yonsei University, Seoul, South Korea.
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Huh
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, South Korea. yjlee1@hanyang.ac.kr.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, South Korea. ksh213@hanyang.ac.kr.|Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. ksh213@hanyang.ac.kr.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Koh
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000069059:Atorvastatin / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016166:Free Radical Scavengers / Q000378:metabolism*; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D018696:Neuroprotective Agents; D000069059:Atorvastatin; D019869:Phosphatidylinositol 3-Kinases
keywords: Amyotrophic lateral sclerosis; Extracellular signal-related kinase; Phosphatidylinositol 3-kinase; Statin