title: Simvastatin Results in a Dose-Dependent Toxic Effect on Spiral Ganglion Neurons in an In Vitro Organotypic Culture Assay.
abstract: Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme necessary for the production of mevalonate. They are widely used as cholesterol-lowering drugs. However, conflicting data about the effect of statins on neuronal cells has been published. To explore the effect of simvastatin on spiral ganglion neurons (SGNs), SG explants of 5-day-old rats were treated with increasing concentrations of simvastatin. In addition, SG explants were treated with mevalonate and with the combination of simvastatin and mevalonate. SGN number, length of the neurites, area of nonneuronal supporting cells, and neuronal survival were analyzed. Simvastatin treatment results in a significant dose-dependent decrease of SG neurite number, length of neurites, area of supporting cells, and SG neuronal survival compared to control. Interestingly, treatment with mevalonate in addition to simvastatin increased SG neuronal survival compared to simvastatin treatment only. However, treatment with mevalonate in addition to simvastatin did not influence SG neurite number, length of neurites, and area of supporting cells compared to simvastatin treatment only. Our results suggest a neurotoxic effect of simvastatin on SGNs in vitro. Neurotoxicity seems to be at least partially mediated by the mevalonate pathway. Therefore, caution is warranted to use simvastatin as a potential otoprotective drug.
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Leitmeyer
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Glutz
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Cristian
authors.initials: C
authors.lastname: Setz
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wieland
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Sulamith
authors.initials: S
authors.lastname: Egloff
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bodmer
authors.affiliation: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Yves
authors.identifier: 0000-0002-6208-6589
authors.initials: Y
authors.lastname: Brand
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008798:Mevalonic Acid / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D019821:Simvastatin / Q000633:toxicity*; D013136:Spiral Ganglion / Q000187:drug effects*
chemical_list: D019821:Simvastatin; D008798:Mevalonic Acid