title: Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease.
abstract: Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid beta(Abeta) (25-35)-injected mice, a rodent model of Alzheimer's disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain. Abeta(25-35)-injected mice showed a cognitive impairment in spontaneous alteration and object recognition tests, the indices of immediate working memory and relatively long-term recognition memory, respectively. As indicated by these tests, the oral administration of perindopril (0.1, 0.3 or 1mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3mg/kg/day) nor enalapril (1, 3 or 10mg/kg/day) had any effect on cognitive performance. Perindopril (1mg/kg/day), imidapril (3mg/kg/day), or enalapril (10mg/kg/day) all inhibited the plasma ACE activities by more than 90%. Using the same dosing regimen, only perindopril inhibited the brain ACE activities by more than 50%, whereas imidapril and enalapril showed much less potent effects. These results suggest that perindopril ameliorated the cognitive impairment in the Alzheimer's disease model mice through the inhibition of brain ACE activity, but not peripheral ACE activity. Based on our observations, we concluded that a centrally active ACE inhibitor, perindopril, may therefore have a beneficial effect on Alzheimer's disease as well as hypertension.
authors.affiliation: Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Sunto-gun, Shizuoka, Japan. kohji.yamada@kyowa-kirin.co.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Syusuke
authors.initials: S
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Takayama
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagata
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Shiro
authors.initials: S
authors.lastname: Shirakura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kanda
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D004656:Enalapril; C065166:imidapril; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril