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Isoflurane produces antidepressant effects inducing BDNF-TrkB signaling in CUMS mice

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Abstract

Rationale

The volatile anesthetic isoflurane is suggested to produce a rapid and robust antidepressive effect in preliminary clinical trials. Recently, isoflurane was found to activate the tropomyosin receptor kinase B (TrkB) signaling which is the underlying mechanism of the rapid antidepressant ketamine.

Objective

Our study investigated the effect of isoflurane anesthesia on chronic unpredictable mild stressed (CUMS) model in mice and verified the role of brain-derived neurotrophic factor (BDNF)/TrkB/ the mammalian target of rapamycin (mTOR) signaling in the antidepressant effect of isoflurane.

Methods

We employed the CUMS model of depression to assess the rapid antidepressant effect of isoflurane by the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). The protein expression of BDNF and TrkB/protein kinase B (PKB or Akt)/mTOR was determined through Western blot. The dendritic spine density in the hippocampus and medial prefrontal cortex (PFC) was measured by the Golgi staining.

Results

A brief burst-suppressing isoflurane anesthesia rapidly reversed the behavioral deficits caused by CUMS procedure, normalized the expression of BDNF and further activated the TrkB signaling pathway in CUMS-induced stressed mice in both prefrontal cortex (PFC) and hippocampus (HC). All of those behavioral and proteomic effects were blocked by K252a, a selective receptor inhibitor of TrkB. Isoflurane significantly promoted the formation of dendritic spines in both medial prefrontal cortex (mPFC), CA1, CA3, and DG of the hippocampus.

Conclusion

Our study indicates that isoflurane exerts a rapid antidepressant-like effect in CUMS depression animal model, and the activation of BDNF/TrkB signaling pathway plays an indispensable role in the biological and behavioral antidepressant effects of isoflurane. A single exposure to isoflurane could repair synaptic damage caused by chronic stimulation.

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Funding

This work was supported by research grants from the National Natural Science Foundation of China (No. 31272397), the Natural Science Foundation of Shandong Province (No. ZR2011CM041), and the Qingdao Postdoctoral Application Research Project (2017).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Qingdao University, Dengzhou Road, Qingdao, 266021, Shandong Province, People’s Republic of China

    Sha-Sha Zhang, Yu-Hua Tian, Jing-Xin Zhao, Xiao-Ming Si & Jing-Yu Jin

  2. Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, Shandong Province, People’s Republic of China

    Song-Jun Jin

  3. Department of Immunization Program, Qingdao Municipal Center For Disease Control & Prevention, Qingdao, 266033, Shandong Province, People’s Republic of China

    Wen-Cheng Wang

  4. Experimental Center for Undergraduates of Pharmacy, School of Pharmacy, Qingdao University, Qingdao, 266021, Shandong Province, People’s Republic of China

    Li Zhang

  5. Department of orthodontics, School of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of China

    Hong Xu

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  1. Sha-Sha Zhang
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Zhang, SS., Tian, YH., Jin, SJ. et al. Isoflurane produces antidepressant effects inducing BDNF-TrkB signaling in CUMS mice. Psychopharmacology 236, 3301–3315 (2019). https://doi.org/10.1007/s00213-019-05287-z

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