Elsevier

Brain Research

Volume 1352, 17 September 2010, Pages 176-186
Brain Research

Research Report
Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease

https://doi.org/10.1016/j.brainres.2010.07.006Get rights and content

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 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. Aβ25–35-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.

Research Highlight

► Perindopril inhibits the angiotensin-converting enzyme (ACE) activity in brain. ► Neither imidapril nor enalapril inhibits the ACE activity in brain. ► Perindopril reverses the impairments of Alzheimer's disease (AD) model mice. ► Neither imidapril nor enalapril reverses the impairments of AD model mice. ► Only the centrally active ACE inhibitors may ameliorate the symptoms of AD.

Introduction

Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure and systemic vascular resistance by blocking the formation of angiotensin II, the endogenous pressor substance of the renin–angiotensin cascade. While these agents have been used primarily in the treatment of hypertension and congestive heart failure, there are some clinical studies in which ACE inhibitors were shown to reduce the incidence of dementia or slow down the rate of cognitive decline in patients with hypertension (Croog et al., 1986, Rozzini et al., 2006, Yasar et al., 2008, Sink et al., 2009).

Perindopril, a long-acting and centrally active ACE inhibitor, has been used as an anti-hypertensive agent all over the world and it has also been reported to reduce risks of dementia and cognitive decline in the patients with recurrent strokes (Tzourio et al., 2003). Furthermore, Ohrui et al. (2004) showed that treatment with centrally active ACE inhibitors, but not non-centrally active ACE inhibitors, could slow down the rate of cognitive decline in mild-to-moderate Alzheimer's disease patients with hypertension. Although this suggests that centrally active ACE inhibitors, usually prescribed as anti-hypertensive drugs, could be expected to have secondary benefits on the symptoms of Alzheimer's disease, the mechanisms responsible for the pro-cognitive effect of this class of drugs have not yet been elucidated.

In the present study, we determined the effect of sub-chronic treatment with perindopril, imidapril and enalapril, on immediate working memory and relatively long-term recognition memory in a mouse model of Alzheimer's disease. We also measured the brain ACE activity under the same dosing regimen to elucidate whether ACE inhibition in the brain may have an important effect on the cognitive function.

Section snippets

Perindopril, but neither imidapril nor enalapril, eliminated working memory deficits in Alzheimer's disease model mice as determined using the spontaneous alteration test

We first examined immediate working memory deficits after intracerebroventricular (i.c.v.) administration of amyloid β (Aβ)25–35 using the spontaneous alteration test. Four days after Aβ25–35-injection, the percent of the spontaneous alteration behavior in the Aβ25–35-injected mice treated with vehicle was significantly lower than that in the control mice that did not receive the Aβ25–35 injection (Figs. 2A, C, and E), while there was no significant difference observed in the number of total

Discussion

In the present study, the effects of sub-chronic treatment with a centrally active ACE inhibitor, perindopril, on the cognitive performance were evaluated using two different behavioral paradigms (spontaneous alteration test and ORT) in a mouse model of Alzheimer's disease. Moreover, the effects of perindopril on these mice were compared with those of two non-centrally active ACE inhibitors, imidapril or enalapril. We also determined the ACE activity in both the plasma and the brain following

Materials

Perindopril erbumine (Nihon Servier, Tokyo, Japan), imidapril hydrochloride (LGM Pharmaceutical Inc., FL, USA) and enalapril maleate (Wako Pure Chemical Industries, Kyoto, Japan), were dissolved in distilled water before use. Aβ25–35 (Bachem AG., Bubendorf, Switzerland) was dissolved in distilled water at a concentration of 1 mg/mL and stored at − 20 °C.

Animals

All experiments on animals were approved by the Committee for Animal Experiments of Kyowa Hakko Kirin Co., Ltd. Male ICR mice were purchased from

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