Atorvastatin protects NSC-34 motor neurons against oxidative stress through the activation of PI3K, ERK and free radical scavenging

Abstract

Objective: Although statins, hydroxymethylglutaryl coenzyme A (HMG-Co A) reductase inhibitors, are generally used to decrease circulating cholesterol levels, they have also been reported to have neuroprotective effects through diverse mechanisms. However, recent reports have shown controversial results as to whether statins /INS;might be harmful in patients with amyotrophic lateral sclerosis (ALS). In this study we investigated the direct effect of atorvastatin on motor neuron /INS;like cells (NSC-34D) against oxidative stress. Material and methods: To evaluate the effect of atorvastatin /INS;and/or hydrogen peroxide on NSC-34D cells, the cells were/INS; treated with several conditions.3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue stain were performed for the evaluation of viability. Free radical level and intracellular signaling proteins were evaluated with fluorescent probe 2′/INS;,7′/INS;-dichlorodihydrofluorescein diacetate (DCFH-DA) and western blotting, respectively. Results: 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 FR180204, a selective extracellular signal-related kinase (ERK) inhibitor. Atorvastatin treatment increased the expression levels of p85aPI3K, phosphorylated /INS;Akt, phosphorylated glycogen synthase kinase-3β,Bcl-2 and phosphorylated ERK which are proteins related to survival, and decreased the levels of cytosolic cytochrome and /INS;cleaved caspase-3, cleaved caspase-9 and Bax which are associated with death, in oxidative stress-injured NSC-34D cells. Conclusion: We conclude that atorvastatin has neuroprotective effect against oxidative stress in motor neurons via the activation of the PI3K pathway, ERK pathway and free radical scavenging. These findings indicate that statins could be helpful in protecting motor neurons