Transcript The antioxidants alpha-lipoic acid and N
The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. Susan A. Farr, et al. • Free radical damage from oxidative stress (Reactive oxygen species, ROS) has long been thought to play an important role in age-related neurodegenerative disorders • Free radicals are produced by the mitochondria in cells as a side effect of energy production from food. • Emerging consensus that free radicals play a causative role in many diseases • Free radical-mediated damage to neuronal membrane is implicated in the etiology of Alzheimer’s disease. • amyloid beta protein, a 39 to 43 amino acid long protein, is the principal component of senile plaques in the AD brain • Molecular and genetic evidence indicate that amyloid beta is central to the pathogenesis of AD. • amyloid beta is a generator of free radicals, and induces oxidative stress damage to neurons in vitro. • Antioxidants have been shown to both prevent and reverse memory deficits caused by free radicals. • Alpha lipoic acid (LA) and N-acetylcysteine (NAC) are anti-oxidants used to combat oxidative-stress induced cell damage. • Studies indicate that both LA and NAC protect against oxidative stress in both peripheral and central nervous system. • Both compounds have been found to reverse age-related impairments of memory in mice. • The SAMP8 strain of mice are a model of Alzheimer’s disease, with elevated levels of amyloid-beta and deficits of learning and memory at a young age. • Decreasing amyloid beta with antibody or antisense RNA improves learning and memory, indicating that amyloid beta is a useful drug target in this model. • SAMP8 mice have elevated free radical production in the CNS, associated with mitochondrial dysfunction. • Farr et al. examined effects of LA and NAC in • T-maze learning task (foot-shock avoidance) • Lever press learning task (food reward) • Ability of NAC to cross the blood-brain barrier • Ability of LA to reverse markers of oxidative stress Results: LA and learning • LA improved performance in T-maze learning task • 12-month old SAMP8 mice that received LA required significantly fewer training trials to learn the maze than did untreated 12-month old mice • 12-month old SAMP8 mice that received LA did not differ significantly in performance from 4month old untreated mice. • 12-month old LA-treated SAMP8 mice learned to get significantly more rewards in the lever-press than did untreated 12-month old mice, but not as many as 4-month old mice. Results: NAC and learning • NAC improved performance in T-maze learning task • 12-month old SAMP8 mice that received NAC required significantly fewer training trials to learn the maze than did untreated 12-month old mice • 12-month old SAMP8 mice that received NAC did not differ significantly in performance from 4month old untreated mice. • 12-month old NAC-treated SAMP8 mice learned to get significantly more rewards in the leverpress than did untreated 12-month old mice, but not as many as 4-month old mice. • NAC was able to cross the blood-brain barrier • LA reduced several measures of oxidative stress • Results support the hypothesis that oxidative stress can lead to cognitive dysfunction and evidence for a therapeutic function for antioxidants, particularly LA and NAC.