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Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1

  • Author Footnotes
    1 HL and P-FW contributed equally to this work.
    Han Luo
    Footnotes
    1 HL and P-FW contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Author Footnotes
    1 HL and P-FW contributed equally to this work.
    Peng-Fei Wu
    Footnotes
    1 HL and P-FW contributed equally to this work.
    Affiliations
    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
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  • Yu Cao
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Ming Jin
    Affiliations
    Department of Pharmaceutics, College of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Tian-Tian Shen
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Ji Wang
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Jian-Geng Huang
    Affiliations
    Department of Pharmaceutics, College of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Qian-Qian Han
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Jin-Gang He
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Si-Long Deng
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Lan Ni
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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  • Zhuang-Li Hu
    Affiliations
    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
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  • Li-Hong Long
    Affiliations
    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
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  • Fang Wang
    Correspondence
    Address correspondence to Jian-Guo Chen, M.D., Ph.D., or Fang Wang, M.D., Ph.D., Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, China 430030.
    Affiliations
    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

    The Collaborative-Innovation Center for Brain Science, Wuhan, Hubei, China
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  • Jian-Guo Chen
    Correspondence
    Address correspondence to Jian-Guo Chen, M.D., Ph.D., or Fang Wang, M.D., Ph.D., Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, China 430030.
    Affiliations
    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

    The Collaborative-Innovation Center for Brain Science, Wuhan, Hubei, China
    Search for articles by this author
  • Author Footnotes
    1 HL and P-FW contributed equally to this work.
Published:February 18, 2020DOI:https://doi.org/10.1016/j.biopsych.2020.02.005

      Abstract

      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.

      Keywords

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      Linked Article

      • Bringing in the ACE(i): Angiotensin-Converting Enzyme Inhibitors as Antidepressants
        Biological PsychiatryVol. 88Issue 5
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          The successful treatment of depression remains limited because approximately 50% of patients do not respond to currently approved therapeutics. Even when effective, most of the pharmacologic interventions take weeks to have effects. The widespread occurrence of depression demands more effective drugs that work rapidly, and recent results with ketamine have invigorated the field (1). However, it remains likely that there will be no magic bullet for such a complex and diverse disorder, and efforts to identify additional therapeutic avenues are both important and necessary.
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