Research Report Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease Koji Yamada a, ⁎ , Shinichi Uchida a , Syusuke Takahashi b , Makoto Takayama a , Yoshinori Nagata b , Nobuyuki Suzuki c , Shiro Shirakura a , Tomoyuki Kanda a a Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan b Pharmacokinetic Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan c Drug Discovery Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan ARTICLE INFO ABSTRACT Article history: Accepted 6 July 2010 Available online 31 July 2010 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 β(Aβ) 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. Aβ 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 1 mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3 mg/kg/day) nor enalapril (1, 3 or 10 mg/kg/day) had any effect on cognitive performance. Perindopril (1 mg/kg/day), imidapril (3 mg/kg/day), or enalapril (10 mg/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. © 2010 Elsevier B.V. All rights reserved. Keywords: Cognitive impairment Spontaneous alteration test Object recognition test Imidapril Enalapril Amyloid β 25–35 -injected mouse BRAIN RESEARCH 1352 (2010) 176 – 186 ⁎ Corresponding author. Fax: +81 55 986 7430. E-mail address: kohji.yamada@kyowa-kirin.co.jp (K. Yamada). Abbreviations: Aβ, amyloid β; APP, amyloid precursor protein; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; i.c.v., intracerebroventricular; ORT, object recognition test; s.i.d, single daily 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.07.006 available at www.sciencedirect.com www.elsevier.com/locate/brainres