Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: A novel mechanism of action |
| |
| Authors: | Eugenio Barone Giovanna Cenini Fabio Di Domenico Sarah Martin Rukhsana Sultana Cesare Mancuso Michael Paul Murphy Elizabeth Head D Allan Butterfield |
| |
| Institution: | 1. Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA;2. Institute of Pharmacology, Catholic University School of Medicine, Largo F. Vito, 1, 00168 Roma, Italy;3. Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy;4. Department of Molecular and Biomedical Pharmacology, and Sanders-Brown Center on Aging University of Kentucky, Lexington, KY, USA;5. Department of Molecular and Cellular Biochemistry, and Sanders-Brown Center on Aging University of Kentucky, Lexington, KY, USA;1. Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium;2. Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium;3. de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 74, 1200 Brussels, Belgium;1. Department of Neuroscience, Georgetown University Medical Center, United States;1. Pharmacology Department, Faculty of Medicine, Ain Shams University, Egypt;2. Armed Forces College of Medicine, Egypt;3. Biochemistry Department, Modern University of Technology and Information, Egypt |
| |
| 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. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
