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.

Curcumin-Mediated Neuroprotection Against Amyloid-β-Induced Mitochondrial Dysfunction Involves the Inhibition of GSK-3β

“…The dyshomostasis of oxidative stress is one of the key factors that induce mitochondrial apoptosis, and increasing evidence indicates that the level of oxidative stress on brain tissue is upregulated during the course of AD [28][29][30].…”

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

“…Because of the fact that both hyperlipidemia as well as oxidative stress is prominent risk factors in the pathogenesis of dementia, rosuvastatin -because of its dual action on both LDL-C and ROS -is an important prospective molecule for the treatment of cognitive impairment. Additionally, atorvastatin has also exhibited anti-oxidative, anti-nitrosative action, and neuroprotective role in preclinical studies [24,25]. Piracetam -a nootropic drug -was used as a positive control as it has proven activity in alleviating cognitive impairment [26].…”

Statins and Reduction of Oxidative Stress in the Aged Brain

“…Moreover, atorvastatin was neuroprotective against cell degeneration induced by Aβ, reducing inflammatory and oxidative responses [25]. Long-term treatment with atorvastatin significantly reduced lipoperoxidation, protein oxidation, and nitration in the mouse brain, despite the lack of change in Aβ levels [26].…”