Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo.
Amyloid beta-peptide (A beta), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of A beta-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of A beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with A beta-(40-1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with A beta-(1-42). Potent antioxidants idebenone and alpha-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in A beta-(1-42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of A beta infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of A beta-(1-42)-infused rats did not differ from those in control animals, and neither idebenone nor alpha-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and alpha-tocopherol prevents learning and memory deficits caused by A beta.
Yamada
K
K
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Tanaka
T
T
Han
D
D
Senzaki
K
K
Kameyama
T
T
Nabeshima
T
T
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D004347:Drug Interactions; D007276:Injections, Intraventricular; D015227:Lipid Peroxidation / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000031:analogs & derivatives; D014810:Vitamin E / Q000494:pharmacology*