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 4- month 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 4- month old untreated mice. 12-month old NAC-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.

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.