The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice.
Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.
Farr
Susan A
SA
Geriatric Research Education and Clinical Center (GRECC), VA Medical Center (151/JC), 915 N. Grand Boulevard, St. Louis, MO 63109, USA. farrsa52@aol.com
Poon
H Fai
HF
Dogrukol-Ak
Dilek
D
Drake
Jeniffer
J
Banks
William A
WA
Eyerman
Edward
E
Butterfield
D Allan
DA
Morley
John E
JE
D000111:Acetylcysteine / Q000627:therapeutic use*; D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001070:Appetitive Behavior / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants; D018384:Oxidative Stress / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D008063:Thioctic Acid / Q000627:therapeutic use*; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D008063:Thioctic Acid; D000111:Acetylcysteine