Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35).
Selegiline, an irreversible inhibitor of monoamine oxidase B used in the treatment of Parkinson's disease, has been demonstrated to have a potential cognition-improving effect in patients with Alzheimer's disease (AD) undergoing treatment with an acetylcholinesterase inhibitor donepezil. To confirm such clinical events, we investigated whether co-administration of donepezil with selegiline had a synergistic cognition-improving effect in an animal model of AD. Intracerebroventricular injection of amyloid beta protein fragment 25-35 [Abeta(25-35)] induced impairment of learning and memory in a Y-maze, novel object recognition and contextual fear conditioning tests. Either donepezil or selegiline alone improved the cognitive impairments in the Y-maze and conditioned fear learning tasks in Abeta(25-35)-injected mice, whereas donepezil, but not selegiline, failed to improve the impairment in a novel object recognition task. Co-administration of donepezil with selegiline, at doses that do not exert efficacy individually, significantly improved the deficits in all three tests, indicating a synergistic cognition-improving effect. These alleviating effects were antagonized by pretreatment with a muscarinic receptor antagonist scopolamine and a dopamine receptor antagonist haloperidol. These results suggest that selegiline potentiates the effect of donepezil on the cognitive impairment, and that the synergistic effect may be mediated through both the cholinergic and dopaminergic systems.
Tsunekawa
Hiroko
H
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan.
Noda
Yukihiro
Y
Mouri
Akihiro
A
Yoneda
Fumio
F
Nabeshima
Toshitaka
T
D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D016229:Amyloid beta-Peptides; D000818:Animals; D001245:Association Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D021641:Recognition, Psychology / Q000187:drug effects; D012642:Selegiline / Q000008:administration & dosage / Q000494:pharmacology*; D016037:Single-Blind Method; D018709:Statistics, Nonparametric
D016229:Amyloid beta-Peptides; D007189:Indans; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; D010880:Piperidines; C074636:amyloid beta-protein (25-35); D012642:Selegiline; D000077265:Donepezil