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

  • Sha-Sha Zhang
  • Yu-Hua Tian
  • Song-Jun Jin
  • Wen-Cheng Wang
  • Jing-Xin Zhao
  • Xiao-Ming Si
  • Li Zhang
  • Hong Xu
  • Jing-Yu JinEmail author
Original Investigation



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.


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.


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.


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.


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.


Isoflurane Rapid antidepressant activity Chronic unpredictable mild stressed Brain-derived neurotrophic factor Tropomyosin receptor kinase B Dendritic spine density 


Funding information

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).

Compliance with ethical standards

Conflict of interests

The authors declare that they have no conflict of interest.

Supplementary material

213_2019_5287_MOESM1_ESM.pdf (83 kb)
ESM 1 (PDF 82 kb)


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Authors and Affiliations

  1. 1.Department of Pharmacology, School of PharmacyQingdao UniversityQingdaoPeople’s Republic of China
  2. 2.Key Laboratory of Experimental Marine Biology, Institute of OceanologyChinese Academy of SciencesQingdaoPeople’s Republic of China
  3. 3.Department of Immunization Program, Qingdao Municipal Center For Disease Control & PreventionQingdaoPeople’s Republic of China
  4. 4.Experimental Center for Undergraduates of Pharmacy, School of PharmacyQingdao UniversityQingdaoPeople’s Republic of China
  5. 5.Department of orthodontics, School of StomatologyThe Affiliated Hospital of Qingdao University, Qingdao UniversityQingdaoPeople’s Republic of China

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