Obara Keisuke, Mori Haruka, Ihara Suzune, Yoshioka Kento, Tanaka Yoshio
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University.
Biol Pharm Bull. 2024;47(1):328-333. doi: 10.1248/bpb.b23-00719.
Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10 M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC value being 4.57 ± 0.02. The pIC values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10 M (sertraline and buspirone), ≥10 M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10 M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.
阿尔茨海默病（AD）伴有痴呆的行为和心理症状（BPSD），使用抗抑郁药、催眠药和抗焦虑药等精神药物治疗通常可缓解这些症状。如果这些药物还能抑制乙酰胆碱酯酶（AChE）活性，它们可能通过增加脑内乙酰胆碱浓度来抑制AD的进展。我们测试了31种抗抑郁药、21种催眠药和12种抗焦虑药对重组人AChE（rhAChE）活性的潜在抑制作用。在10μM浓度下，22种抗抑郁药、19种催眠药和11种抗焦虑药对rhAChE活性的抑制率<20%，而9种抗抑郁药（氯米帕明、阿莫沙平、塞替普汀、奈法唑酮、帕罗西汀、舍曲林、西酞普兰、艾司西酞普兰和米氮平）、2种催眠药（三唑仑和溴替唑仑）和1种抗焦虑药（丁螺环酮）对rhAChE活性的抑制率≥20%。溴替唑仑（≥10μM）对rhAChE活性的抑制作用比其他药物更强，其pIC值为4.57±0.02。其他药物的pIC值<4，它们在以下浓度下对rhAChE表现出抑制活性：≥3×10μM（舍曲林和丁螺环酮）、≥10μM（阿莫沙平、奈法唑酮、帕罗西汀、西酞普兰、艾司西酞普兰、米氮平和三唑仑）以及≥3×10μM（氯米帕明和塞替普汀）。在这些药物中，只有奈法唑酮在临床剂量可达到的血药浓度范围内抑制rhAChE活性。因此，奈法唑酮不仅可以通过其抗抑郁作用改善BPSD的抑郁症状，还可以通过其AChE抑制作用减缓AD认知症状的进展。
