BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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血管紧张素转换酶抑制剂通过 mTORC1 的缓激肽依赖性激活快速改善抑郁型行为

背景血管紧张素转换酶抑制剂(ACEI)是广泛规定的抗高血压药。有趣的是，病例报告和临床试验表明，包括卡托普利和赖诺普利在内的 ACEI 可能对某些患者具有快速提升情绪的作用，但很少有实验研究调查它们作为速效抗抑郁药的价值。方法本研究包括一系列使用生化分析、免疫组织化学和行为技术的实验，以检查卡托普利对两种动物模型（慢性不可预测压力模型和慢性社会失败压力模型）抑郁样行为的影响和机制。结果 卡托普利（19.5 或 39 mg/kg，腹腔注射）在慢性不可预测应激模型下治疗的小鼠和慢性社交失败应激模型下治疗的小鼠中发挥快速抗抑郁活性。药代动力学分析表明，卡托普利穿过血脑屏障，而赖诺普利（另一种具有更好血脑屏障通透性的 ACEI）在相同摩尔当量剂量下发挥更快、更持久的作用。这种抗抑郁作用似乎与肾素-血管紧张素系统无关，但取决于缓激肽 (BK) 系统，因为在应激小鼠中检测到的 BK 降低可以被卡托普利逆转。BK 下游效应子 Cdc42（细胞分裂控制蛋白 42）同系物的功能减退导致了应激诱导的树突棘丢失，卡托普利通过激活 mTORC1（雷帕霉素复合物 1 的哺乳动物靶标）途径迅速逆转了这一过程。结论我们的研究结果表明，mTORC1 的 BK 依赖性激活可能代表了抗抑郁药理学的潜在机制。考虑到它们的可负担性和可用性，ACEI 可能会成为一种新型的速效抗抑郁药，特别是对于患有抑郁症和高血压的患者。