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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

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.

Keywords

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

Notes

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)

References

  1. Abdallah CG, Sanacora G, Duman RS, Krystal JH (2018) The neurobiology of depression, ketamine and rapid-acting antidepressants: is it glutamate inhibition or activation? Pharmacol Ther 190:148–158CrossRefGoogle Scholar
  2. Abelaira HM, Réus GZ, Neotti MV, Quevedo J (2014) The role of mTOR in depression and antidepressant responses. Life Sci 101(1–2):10–14CrossRefGoogle Scholar
  3. Abrams R (2002) Electroconvulsive therapy (ECT) practice in metropolitan New York community hospitals. Psychol Med 32(7):1323–1324 author reply 24-6CrossRefGoogle Scholar
  4. Adell A, Castro E, Celada P, Bortolozzi A, Pazos A, Artigas F (2005) Strategies for producing faster acting antidepressants. Drug Discov Today 10(8):578–585CrossRefGoogle Scholar
  5. Antila H, Ryazantseva M, Popova D, Sipilä P, Guirado R, Kohtala S, Yalcin I, Lindholm J, Vesa L, Sato V, Cordeira J, Autio H, Kislin M, Rios M, Joca S, Casarotto P, Khiroug L, Lauri S, Taira T, Castrén E, Rantamäki T (2017) Isoflurane produces antidepressant effects and induces TrkB signaling in rodents. Sci Rep 7(1):7811CrossRefGoogle Scholar
  6. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475(7354):91–95CrossRefGoogle Scholar
  7. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354CrossRefGoogle Scholar
  8. Brown PL, Zanos P, Wang L, Elmer GI, Gould TD, Shepard PD (2018) Isoflurane but not halothane prevents and reverses helpless behavior: a role for EEG burst suppression? Int J Neuropsychopharmacol 21:777–785CrossRefGoogle Scholar
  9. Cai Y, Peng Z, Guo H, Wang F, Zeng Y (2017) TREK-1 pathway mediates isoflurane-induced memory impairment in middle-aged mice. Neurobiol Learn Mem 145:199–204CrossRefGoogle Scholar
  10. Carl C, Engelhardt W, Teichmann G, Fuchs G (1988) Open comparative study with treatment-refractory depressed patients: electroconvulsive therapy--anesthetic therapy with isoflurane (preliminary report). Pharmacopsychiatry 21(6):432–433CrossRefGoogle Scholar
  11. Castren E, Voikar V, Rantamaki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7(1):18–21CrossRefGoogle Scholar
  12. Chandran A, Iyo AH, Jernigan CS, Legutko B, Austin MC, Karolewicz B (2013) Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuro-Psychopharmacol Biol Psychiatry 40:240–245CrossRefGoogle Scholar
  13. Cryan JF, Mombereau C (2004) In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry 9:326–357CrossRefGoogle Scholar
  14. Der-Avakian A, Markou A (2012) The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci 35(1):68–77CrossRefGoogle Scholar
  15. Di Lieto A et al (2012) The responsiveness of TrkB to BDNF and antidepressant drugs is differentially regulated during mouse development. PLoS One 7(3):e32869CrossRefGoogle Scholar
  16. Dincheva I, Lynch NB, Lee FS (2016) The role of BDNF in the development of fear learning. Depress Anxiety 33(10):907–916CrossRefGoogle Scholar
  17. Dincheva I, Yang J, Li A, Marinic T, Freilingsdorf H, Huang C, Casey BJ, Hempstead B, Glatt CE, Lee FS, Bath KG, Jing D (2017) Effect of early-life fluoxetine on anxiety-like behaviors in BDNF Val66Met mice. Am J Psychiatry 174(12):1203–1213CrossRefGoogle Scholar
  18. Drevets WC (1998) Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med 49:341–361CrossRefGoogle Scholar
  19. Engelhardt W, Carl G, Hartung E (1993) Intra-individual open comparison of burst-suppression-isoflurane-anaesthesia versus electroconvulsive therapy in the treatment of severe depression. Eur J Anaesthesiol 10(2):113–118Google Scholar
  20. Garcia LS et al (2009) Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 33(3):450–455CrossRefGoogle Scholar
  21. Greenberg LB et al (1987) Isoflurane anesthesia therapy: a replacement for ECT in depressive disorders? Convuls Ther 3(4):269–277Google Scholar
  22. Heurteaux C, Lucas G, Guy N, el Yacoubi M, Thümmler S, Peng XD, Noble F, Blondeau N, Widmann C, Borsotto M, Gobbi G, Vaugeois JM, Debonnel G, Lazdunski M (2006) Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9(9):1134–1141CrossRefGoogle Scholar
  23. Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33(2):67–75CrossRefGoogle Scholar
  24. Ignacio ZM et al (2016) New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. Br J Clin Pharmacol 82(5):1280–1290CrossRefGoogle Scholar
  25. Kasmi Y (2002) Electroconvulsive therapy and cognitive function. Ir J Psychol Med 19(2):70–71CrossRefGoogle Scholar
  26. Kato T, et al. (2017) ‘BDNF release and signaling are required for the antidepressant actions of GLYX-13’, Mol PsychiatryGoogle Scholar
  27. Kohtala S, Theilmann W, Suomi T, Wigren HK, Porkka-Heiskanen T, Elo LL, Rokka A, Rantamäki T (2016) Brief isoflurane anesthesia produces prominent Phosphoproteomic changes in the adult mouse Hippocampus. ACS Chem Neurosci 7(6):749–756CrossRefGoogle Scholar
  28. Koinig G, Langer G (1988) Might “isoflurane Narcotherapy” replace ECT? Convuls Ther 4(1):98–99Google Scholar
  29. Langer G, Neumark J, Koinig G, Graf M, Schönbeck G (1985) Rapid psychotherapeutic effects of anesthesia with isoflurane (ES narcotherapy) in treatment-refractory depressed patients. Neuropsychobiology 14(3):118–120CrossRefGoogle Scholar
  30. Langer G, Karazman R, Neumark J, Saletu B, Schönbeck G, Grünberger J, Dittrich R, Petricek W, Hoffmann P, Linzmayer L, Anderer P, Steinberger K (1995) Isoflurane narcotherapy in depressive patients refractory to conventional antidepressant drug treatment. A double-blind comparison with electroconvulsive treatment. Neuropsychobiology 31(4):182–194CrossRefGoogle Scholar
  31. Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS (2015) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18(1):pyu033CrossRefGoogle Scholar
  32. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964CrossRefGoogle Scholar
  33. Li N, He X, Zhang Y, Qi X, Li H, Zhu X, He S (2011a) Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine. Int J Neuropsychopharmacol 14(8):1091–1098CrossRefGoogle Scholar
  34. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS (2011b) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69(8):754–761CrossRefGoogle Scholar
  35. Lisanby SH (2007) Electroconvulsive therapy for depression. N Engl J Med 357(19):1939–1945CrossRefGoogle Scholar
  36. Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS (2006) Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26(30):7870–7874CrossRefGoogle Scholar
  37. Liu RJ, Aghajanian GK (2008) Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci U S A 105(1):359–364CrossRefGoogle Scholar
  38. Louhivuori V, Vicario A, Uutela M, Rantamäki T, Louhivuori LM, Castrén E, Tongiorgi E, Åkerman KE, Castrén ML (2011) BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse. Neurobiol Dis 41(2):469–480CrossRefGoogle Scholar
  39. Malenka RC, Nestler EJ, Hyman SE (2009) Chapter 8: atypical neurotransmitters. In: Brown RY, Sydor A (eds) Molecular neuropharmacology: a Foundation for clinical neuroscience (2nd ed.). McGraw-Hill Medical, New YorkGoogle Scholar
  40. Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde YA (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11(2):131–133CrossRefGoogle Scholar
  41. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y, Posada-Villa J, Sagar R, Wells JE, Zarkov Z (2011) Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 68(3):241–251CrossRefGoogle Scholar
  42. Molendijk ML, van Tol MJ, Penninx BWJH, van der Wee NJA, Aleman A, Veltman DJ, Spinhoven P, Elzinga BM (2012) BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity. Transl Psychiatry 2:e74CrossRefGoogle Scholar
  43. Morris AJ, Roche SA, Bentham P, Wright J (2002) A dental risk management protocol for electroconvulsive therapy. J ECT 18(2):84–89CrossRefGoogle Scholar
  44. Mu RH, Fang XY, Wang SS, Li CF, Chen SM, Chen XM, Liu Q, Li YC, Yi LT (2016) Antidepressant-like effects of standardized gypenosides: involvement of brain-derived neurotrophic factor signaling in hippocampus. Psychopharmacology 233(17):3211–3221CrossRefGoogle Scholar
  45. Numakawa T, Adachi N, Richards M, Chiba S, Kunugi H (2013) Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system. Neuroscience 239:157–172CrossRefGoogle Scholar
  46. Nutt DJ, Ballenger JC, Sheehan D, Wittchen HU (2002) Generalized anxiety disorder: comorbidity, comparative biology and treatment. Int J Neuropsychopharmacol 5(4):315–325CrossRefGoogle Scholar
  47. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24(45):10099–10102CrossRefGoogle Scholar
  48. Radley JJ, Morrison JH (2005) Repeated stress and structural plasticity in the brain. Ageing Res Rev 4(2):271–287CrossRefGoogle Scholar
  49. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45(9):1085–1098CrossRefGoogle Scholar
  50. Ramaker MJ, Dulawa SC (2017) Identifying fast-onset antidepressants using rodent models. Mol Psychiatry 22(5):656–665CrossRefGoogle Scholar
  51. Rantamaki T et al (2007) Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 32(10):2152–2162CrossRefGoogle Scholar
  52. Rantamaki T et al (2011) Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade. PLoS One 6(6):e20567CrossRefGoogle Scholar
  53. Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castrén E (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23(1):349–357CrossRefGoogle Scholar
  54. Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18(5–6):391–418CrossRefGoogle Scholar
  55. Si X-M et al. (2018) Low molecular mass chondroitin sulfate suppresses chronic unpredictable mild stress-induced depression-like behavior in mice (68) 361–71Google Scholar
  56. Soares JC, Mann JJ (1997) The anatomy of mood disorders--review of structural neuroimaging studies. Biol Psychiatry 41(1):86–106CrossRefGoogle Scholar
  57. Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P (2004) Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 29(11):2007–2017CrossRefGoogle Scholar
  58. Tadler SC, Mickey BJ (2018) Emerging evidence for antidepressant actions of anesthetic agents. Curr Opin Anaesthesiol 31(4):439–445CrossRefGoogle Scholar
  59. Tadler S, Light A, Hughen R (2009) Isoflurane demonstrates antidepressant-like activity in a mouse model of depression (Abstract). Anesth Analg 108:212Google Scholar
  60. Tan X, du X, Jiang Y, Botchway BOA, Hu Z, Fang M (2018) Inhibition of autophagy in microglia alters depressive-like behavior via BDNF pathway in postpartum depression. Front Psychiatry 9:434CrossRefGoogle Scholar
  61. Theilmann W, Alitalo O, Yorke I, Rantamäki T (2019) Dose-dependent effects of isoflurane on TrkB and GSK3beta signaling: importance of burst suppression pattern. Neurosci Lett 694:29–33CrossRefGoogle Scholar
  62. Vutskits L (2012) General anesthesia: a gateway to modulate synapse formation and neural plasticity? Anesth Analg 115(5):1174–1182CrossRefGoogle Scholar
  63. Vutskits L (2018) General anesthetics to treat major depressive disorder: clinical relevance and underlying mechanisms. Anesth Analg 126(1):208–216CrossRefGoogle Scholar
  64. Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A 104(11):4647–4652CrossRefGoogle Scholar
  65. Weeks HR III et al (2013) Antidepressant and neurocognitive effects of isoflurane anesthesia versus electroconvulsive therapy in refractory depression. PLoS One 8(7):e69809CrossRefGoogle Scholar
  66. WHO ‘Depression Fact Sheet’, [Internet], (updated 22 March 2018a) <http://www.who.int/news-room/fact-sheets/detail/depression>, Accessed 22 MarchGoogle Scholar
  67. WHO ‘Suicide Fact Sheet’ [Internet]. <http://www.who.int/news-room/fact-sheets/detail/depression>, Accessed 24 Aug 2018bGoogle Scholar
  68. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134(4):319–329CrossRefGoogle Scholar
  69. Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52(2):90–110CrossRefGoogle Scholar
  70. Willner P (2017) The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress 6:78–93Google Scholar
  71. Xu A, Cui S, Wang J-H (2015) Incoordination among Subcellular Compartments Is Associated with Depression-Like Behavior Induced by Chronic Mild Stress (19) pyv122Google Scholar
  72. Yang J, Siao CJ, Nagappan G, Marinic T, Jing D, McGrath K, Chen ZY, Mark W, Tessarollo L, Lee FS, Lu B, Hempstead BL (2009) Neuronal release of proBDNF. Nat Neurosci 12(2):113–115CrossRefGoogle Scholar
  73. Ye D, Li Y, Zhang X, Guo F, Geng L, Zhang Q, Zhang Z (2015) TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling. Eur Neuropsychopharmacol 25(12):2426–2436CrossRefGoogle Scholar
  74. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KSS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate Jr CA, Gould TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533(7604):481–486CrossRefGoogle Scholar

Copyright information

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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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