The antioxidants alpha-lipoic acid and N

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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.