title: Atorvastatin treatment in a dog preclinical model of Alzheimer's disease leads to up-regulation of haem oxygenase-1 and is associated with reduced oxidative stress in brain.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Only acetylcholinesterase inhibitors and the NMDA antagonist memantine are approved for AD treatment. Recent preclinical and epidemiological studies proposed statins as novel therapeutics for AD, but the mechanisms of action are still unknown. Here, we demonstrate that atorvastatin (80 mg/d for 14.5 months) treatment resulted in an up-regulation of the inducible isoform of haem oxygenase (HO-1), an enzyme with significant neuroprotective activity. Atorvastatin selectively increased HO-1 in the parietal cortex but not cerebellum. In contrast, HO-2 was increased in cerebellum but not parietal cortex. No changes were observed in HO-1 or HO-2 in the liver. Significant negative correlations between HO-1 and oxidative stress indices and positive correlations with glutathione levels in parietal cortex were found. HO-1 up-regulation significantly correlated with lower discrimination learning error scores in aged beagles. Reference to therapeutic applications of atorvastatin in AD is discussed.
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. dabcns@uky.edu
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069059:Atorvastatin; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004285:Dogs; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007653:Ketocholesterols / Q000378:metabolism; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000447:Aldehydes; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D007653:Ketocholesterols; D011758:Pyrroles; D000069059:Atorvastatin; D051547:Heme Oxygenase-1; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; C003001:7-ketocholesterol