title: Behavioral and quantitative mitochondrial proteome analyses of the effects of simvastatin: implications for models of neural degeneration.
abstract: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, is used for lowering elevated low-density lipoprotein cholesterol concentrations. This translates into reduced cardiovascular disease-related morbidity and mortality, while the drugs' anti-oxidant and anti-inflammatory properties have earmarked it as a potential treatment strategy against various neurological conditions. Statins have been shown to protect neurons from degeneration in a number of animal models. Although no mechanism completely explains the multiple benefits exerted by statins, emerging evidence suggests that in some degenerative and brain injury models, mitochondrial impairment may play a contributive rate. However, [corrected] evidence lacks to support a directly influencing role for statins on mitochondria-related proteins and motor behavior. Mitochondrial dysfunction may increase oxygen free radical production, which in turn leaves cells susceptible to energy failure, apoptosis and related events [corrected] which could prove fatal. The potential link between simvastatin treatment and mitochondrial function would be supported if key mitochondrial proteins were altered by simvastatin exposure. Using mass spectroscopy (MS), we identified 24 mitochondrial proteins that differed significantly (P < 0.05) in relative abundancy as a result of simvastatin treatment. The identified proteins represented many facets of mitochondrial integrity, with the majority forming part of the electron transport chain machinery, which is necessary for energy production. In a follow-up study, we then addressed whether simvastatin is capable of altering sensorimotor function in a mitochondrial toxin-induced animal model. Rats were pre-treated with simvastatin for 14 days, followed by a single unihemispheric (substantia nigra; SN) injection of rotenone, a mitochondrial complex I (Co-I) inhibitor. Results showed that simvastatin improved motor performance in rotenone-infused rats. The data are consistent with the possibility that alteration of mitochondrial function may contribute to the beneficial effects associated with statin use.
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. Ilse.pienaar@dpag.ox.ac.uk
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.forename: Timothy
authors.initials: T
authors.lastname: Schallert
authors.forename: Suzél
authors.initials: S
authors.lastname: Hattingh
authors.forename: William M U
authors.initials: WM
authors.lastname: Daniels
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000187:drug effects* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020543:Proteome / Q000187:drug effects* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012402:Rotenone / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D045222:Electron Transport Chain Complex Proteins; D005609:Free Radicals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D020543:Proteome; D014475:Uncoupling Agents; D012402:Rotenone; D019821:Simvastatin