title: Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: a novel mechanism of action.
abstract: Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss, inability to perform the activities of daily living and personality changes. Unfortunately, drugs effective for this disease are limited to acetylcholinesterase inhibitors that do not impact disease pathogenesis. Statins, which belong to the class of cholesterol-reducing drugs, were proposed as novel agents useful in AD therapy, but the mechanism underlying their neuroprotective effect is still unknown. In this study, we show that atorvastatin may have antioxidant effects, in aged beagles, that represent a natural higher mammalian model of AD. Atorvastatin (80 mg/day for 14.5 months) significantly reduced lipoperoxidation, protein oxidation and nitration, and increased GSH levels in parietal cortex of aged beagles. This effect was specific for brain because it was not paralleled by a concomitant reduction in all these parameters in serum. In addition, atorvastatin slightly reduced the formation of cholesterol oxidation products in cortex but increased the 7-ketocholesterol/total cholesterol ratio in serum. We also found that increased oxidative damage in the parietal cortex was associated with poorer learning (visual discrimination task). Thus, a novel pharmacological effect of atorvastatin mediated by reducing oxidative damage may be one mechanism underlying benefits of this drug in AD.
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.forename: Michael Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D000069059:Atorvastatin; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D008297:Male; D009603:Nitroso Compounds / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000008:administration & dosage*; D011897:Random Allocation
chemical_list: D000975:Antioxidants; D006538:Heptanoic Acids; D009603:Nitroso Compounds; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin