The effect of simvastatin induced neurotoxicity on mitochondrial function in human neuronal cells

Millichap, Lauren, Turton, Nadia, Alomosh, Razan, Heaton, Robert A, Bateman, Amy, Al-Shanti, Nasser, Lightfoot, Adam P ORCID: https://orcid.org/0000-0003-1501-7879, Damiani, Elisabetta, Marcheggiani, Fabio, Orlando, Patrick, Silvestri, Sonia, Tiano, Luca and Hargreaves, Iain P (2025) The effect of simvastatin induced neurotoxicity on mitochondrial function in human neuronal cells. Toxicology Mechanisms and Methods. pp. 1-12. ISSN 1537-6516

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Abstract

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) inhibitors, commonly known as statins, are drugs frequently used in the treatment of hypercholesterolemia and hyperlipidemia. However, the current study has demonstrated that simvastatin induces neurotoxicity and is associated with cellular coenzyme Q10 (CoQ10) depletion. CoQ10 has a significant role in the mitochondrial electron transport chain (ETC), in addition to being a fundamental lipid-soluble antioxidant. Depletion of CoQ10 is frequently associated with impaired mitochondrial function and increased oxidative stress. The aim of this study was to investigate the potential mechanisms of simvastatin-induced neurotoxicity assessing mitochondrial function and evidence of oxidative stress in an in vitro SH-SY5Y human neuronal cell line. Fluorescence studies assessed via flow cytometry determined significant increases in intracellular and mitochondrial reactive oxygen species production following SH-SY5Y treatment with simvastatin compared to control cells. Additionally, spectrophotometric enzyme studies determined a significant (p < 0.0001) inhibition of ETC complex I and II-III activities which accompanied a significant decrease in neuronal CoQ10 content (p < 0.005) and cell viability (p < 0.0001). The results of the present study have indicated evidence of mitochondrial dysfunction and increased oxidative stress, resulting in increased loss of neuronal viability following simvastatin treatment. Thus, these results demonstrate evidence of neurotoxicity associated with statin therapy.