Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, China; Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Biol Psychiatry. 2020 Sep 1;88(5):415-425. doi: 10.1016/j.biopsych.2020.02.005. Epub 2020 Feb 18.
Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants.
The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model.
Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway.
Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension.
血管紧张素转换酶抑制剂（ACEIs）被广泛用于治疗高血压。有趣的是，病例报告和临床试验表明，ACEIs，包括卡托普利和赖诺普利，可能会对某些患者产生快速的情绪提升作用，但很少有实验研究探讨它们作为快速起效抗抑郁药的价值。
本研究由一系列使用生化测定、免疫组织化学和行为技术的实验组成，旨在研究卡托普利对 2 种动物模型（慢性不可预测应激模型和慢性社交挫败应激模型）中抑郁样行为的影响及其机制。
卡托普利（19.5 或 39 mg/kg，腹腔注射）对慢性不可预测应激模型和慢性社交挫败应激模型处理的小鼠表现出快速的抗抑郁活性。药代动力学分析表明，卡托普利能穿过血脑屏障，另一种血脑屏障通透性更好的 ACEI 赖诺普利，以相同摩尔当量剂量给药时，起效更快、作用持续时间更长。这种抗抑郁作用似乎独立于肾素-血管紧张素系统，但依赖于缓激肽（BK）系统，因为应激小鼠中检测到的 BK 减少可以被卡托普利逆转。BK 的下游效应器 Cdc42（细胞分裂控制蛋白 42）同源物的功能低下导致应激诱导的树突棘丢失，而卡托普利通过激活 mTORC1（雷帕霉素靶蛋白复合物 1）通路，迅速逆转了这一现象。
我们的研究结果表明，BK 依赖性激活 mTORC1 可能代表抗抑郁药理学的一个有前途的机制。考虑到它们的可负担性和可得性，ACEIs 可能成为一种新型的快速起效抗抑郁药，特别是对伴有抑郁和高血压的患者。
