ABSTRACT
Title
Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: A novel mechanism of action.
Authors
E. Barone1, E. Head2 and D. A. Butterfield3
1Institute of Pharmacology, Catholic University School of Medicine, Largo F.Vito,1, 00168 Rome, Italy; 2Department of Molecular and Biomedical Pharmacology, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; 3Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
1Institute of Pharmacology, Catholic University School of Medicine, Largo F.Vito,1, 00168 Rome, Italy; 2Department of Molecular and Biomedical Pharmacology, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; 3Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
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. Moreover, AD pathology is characterized by an increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Both ROS and RNS may react with biomolecules including proteins, lipids, carbohydrates, DNA and RNA leading to oxidative damage and cellular dysfunction.Over the last years, the up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO/BVR-A) system was proposed as an early and long-lasting mechanism through which cells counteract oxidative and nitrosative damage. Biliverdin reductase-A plays a main role in the adaptive response to stress by acting at several levels. First, BVR-A reduces HO-derived biliverdin into bilirubin-IX-α, a powerful endogenous antioxidant; second, through its Ser/Thr/Tyr kinase activity BVR-A modulates cell growth and metabolism, thus helping cell to escape from pro-oxidant conditions. In addition, studies performed in our laboratory demonstrated that both ROS and RNS induce post-translational modifications on BVR-A thus affecting its activity in the brain of subjects with AD.
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. Although the statins’ effects on HO-1 protein levels and activity have both proved to be drug- and tissue-type specific, no evidence is available for the brain. Indeed, statins’ effects on HO/BVR-A system were not explored so far. Aged beagles represent a good pre-clinical model of AD because they deposit endogenous levels of beta amyloid peptide (Aβ) of identical sequence to human Aβ as they age and thus are a natural higher mammalian model of aging. Moreover in terms of the pattern and severity of cognitive decline, the aged canine parallels age-associated memory impairment in humans. Recent studies showed that atorvastatin (80 mg/day for 14.5 months) significantly reduced both lipid and protein oxidation as well as protein 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. Moreover, serum CoQ10, was significantly lower in statin treated dogs. Interestingly, an increased oxidative damage in the parietal cortex was associated with poorer learning evaluated in dogs by the visual discrimination task. As regard to HO-1/BVR-A system, a significant increase in HO-1 and BVR-A protein levels was found in parietal cortex of aged beagles. However, BVR-A undergoes post-translational modifications that affect its acitivies. Atorvastatin, significantly increased phosho-Tyr-BVR-A (pTyr-BVR-A) and slightly reduced BVR-A nitration. As a consequence, reductase activity was increased in parietal cortex, although this result didn’t reach statistical significance. An interesting corollary was that, after atorvastatin treatment, increased BVR-A protein levels and activity significantly correlated with lower oxidative damage in the parietal cortex. At the same time, higher BVR-A protein levels and phosphorylation on Tyr residues were associated with an improvement in cognitive functions . Thus, a novel pharmacological effect of atorvastatin mediated by reducing oxidative damageand, at least in part, by the activation of HO-1/BVR-A system, may be one mechanism underlying benefits of this drug in AD.
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. Although the statins’ effects on HO-1 protein levels and activity have both proved to be drug- and tissue-type specific, no evidence is available for the brain. Indeed, statins’ effects on HO/BVR-A system were not explored so far. Aged beagles represent a good pre-clinical model of AD because they deposit endogenous levels of beta amyloid peptide (Aβ) of identical sequence to human Aβ as they age and thus are a natural higher mammalian model of aging. Moreover in terms of the pattern and severity of cognitive decline, the aged canine parallels age-associated memory impairment in humans. Recent studies showed that atorvastatin (80 mg/day for 14.5 months) significantly reduced both lipid and protein oxidation as well as protein 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. Moreover, serum CoQ10, was significantly lower in statin treated dogs. Interestingly, an increased oxidative damage in the parietal cortex was associated with poorer learning evaluated in dogs by the visual discrimination task. As regard to HO-1/BVR-A system, a significant increase in HO-1 and BVR-A protein levels was found in parietal cortex of aged beagles. However, BVR-A undergoes post-translational modifications that affect its acitivies. Atorvastatin, significantly increased phosho-Tyr-BVR-A (pTyr-BVR-A) and slightly reduced BVR-A nitration. As a consequence, reductase activity was increased in parietal cortex, although this result didn’t reach statistical significance. An interesting corollary was that, after atorvastatin treatment, increased BVR-A protein levels and activity significantly correlated with lower oxidative damage in the parietal cortex. At the same time, higher BVR-A protein levels and phosphorylation on Tyr residues were associated with an improvement in cognitive functions . Thus, a novel pharmacological effect of atorvastatin mediated by reducing oxidative damageand, at least in part, by the activation of HO-1/BVR-A system, may be one mechanism underlying benefits of this drug in AD.