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Antidepressant-like Effect of 3-n-Butylphthalide in Rats Exposed to Chronic Unpredictable Mild Stress: Modulation of Brain-Derived Neurotrophic Factor Level and mTOR Activation in Cortex

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Abstract

3-n-Butylphthalide (NBP), an extract from seeds of Apium graveolens Linn. (Chinese celery), has been demonstrated to have antidepressant effects in suspension chronic-stressed rats by our group. The purpose of this study was to investigate the possible involvement of brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the antidepressant mechanism of NBP. Chronic unpredictable mild stress (CUMS) was applied for 6 weeks to induced a depressive-like behavior, characterized by decreased locomotor activity, sucrose preference and the NE, DA and 5-HT levels in cortex. Oral treatment with NBP (30 or 100 mg/kg, p.o.), similarly to fluoxetine (2 mg/kg, p.o.), can prevention of these alterations. The NBP (30 or 100 mg/kg, p.o.) reversed the decrease in the BDNF, p-ERK, mTOR and synapsin-1 protein levels in rat cortex caused by CUMS. And rapamycin, an mTOR inhibitor, completely inhibited the antidepressant-like activity of NBP in vivo. In conclusion, these findings indicate that NBP treatment attenuated the depression-like behaviors through the modulation of serotonergic system and BDNF-ERK-mTOR signaling in rat.

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References

  1. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC (2015) The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry 76:155–162. https://doi.org/10.4088/JCP.14m09298

    Article  PubMed  Google Scholar 

  2. Bostwick JM (2010) A generalist’s guide to treating patients with depression with an emphasis on using side effects to tailor antidepressant therapy. Mayo Clin Proc 85:538–550. https://doi.org/10.4065/mcp.2009.0565

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jasiak NM, Bostwick JR (2014) Risk of QT/QTc prolongation among newer non-SSRI antidepressants. Ann Pharmacother 48:1620–1628. https://doi.org/10.1177/1060028014550645

    Article  PubMed  CAS  Google Scholar 

  4. Ma S, Xu S, Liu B, Li J, Feng N, Wang L, Wang X (2009) Long-term treatment of l-3-n-butylphthalide attenuated neurodegenerative changes in aged rats. Naunyn Schmiedebergs Arch Pharmacol 379:565–574. https://doi.org/10.1007/s00210-009-0398-8

    Article  PubMed  CAS  Google Scholar 

  5. Liu CL, Liao SJ, Zeng JS, Lin JW, Li CX, Xie LC, Shi XG, Huang RX (2007) dl-3n-Butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP. J Neuro Sci 260:106–113. https://doi.org/10.1016/j.jns.2007.04.025

    Article  CAS  Google Scholar 

  6. Peng Y, Xing C, Lemere CA, Chen G, Wang L, Feng Y, Wang X (2008) 1-3-n-Butylphthalide ameliorates beta-amyloid-induced neuronal toxicity in cultured neuronal cells. Neurosci Lett 434:224–229. https://doi.org/10.1016/j.neulet

    Article  PubMed  CAS  Google Scholar 

  7. Yan C, Feng Y, Zhang J (1998) Effects of dl-3-n-butylphthalide on regional cerebral blood flow in right middle cerebral artery occlusion rats. Acta Pharmacol Sin 01:36–39. https://doi.org/10.1016/S0168-3659(97)00217-4

    Article  Google Scholar 

  8. Peng Y, Zeng X, Feng Y, Wang X (2004) Antiplatelet and antithrombotic activity of l-3-n-butylphthalide in rats. J Cardiovasc Pharmacol 43:876–881. https://doi.org/10.1097/00005344-200406000-00018

    Article  PubMed  CAS  Google Scholar 

  9. Ye J, Zhai L, Zhang S, Zhang Y, Chen L, Hu L et al (2015) dl-3-n-Butylphthalide inhibits platelet activation via inhibition of cPLA2-mediated TXA2 synthesis and phosphodiesterase. Platelets 26:736–744. https://doi.org/10.3109/09537104.2014.989826

    Article  PubMed  CAS  Google Scholar 

  10. Wang Y, Qi W, Zhang L, Ying Z, Sha O, Li C et al (2017) The novel targets of dl-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study. Quant Imaging Med Surg 7:532–536. https://doi.org/10.21037/qims.2017.10.08

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ji X-C, Zhao W-H, Cao D-X, Shi Q-Q (2011) Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1. Acta Pharmacol Sin 32:182–187

    Article  CAS  Google Scholar 

  12. Xu LL, Wang XY, Zhang XY (2016) Antidepression effect of 3-n-Butylphathlide in mice and rat. J Yichun Univ 38:23–27

    CAS  Google Scholar 

  13. Phillips C (2017) Brain-derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection. Neural Plast 2017:7260130. https://doi.org/10.1155/2017/7260130

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. Cell Sci 122:3589–3594. https://doi.org/10.1242/jcs.035105

    Article  CAS  Google Scholar 

  15. Duman RS, Li NX, Liu RJ, Duric V, Aghajanian G (2012) The mTOR Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 62:35–41. https://doi.org/10.1016/j.neuropharm.2011.08.044

    Article  PubMed  CAS  Google Scholar 

  16. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ (2014) Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 29:419–423. https://doi.org/10.1016/j.eurpsy.2013.10.005

    Article  PubMed  CAS  Google Scholar 

  17. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134:319–329. https://doi.org/10.1007/s002130050456

    Article  PubMed  CAS  Google Scholar 

  18. Kulkarni SK, Dandiya PC (1973) Effect of antidepressant agents on open field behaviour in rats. Psychopharmacologia 33:333–338. https://doi.org/10.1007/BF00437510

    Article  PubMed  CAS  Google Scholar 

  19. Willner P, Muscat R, Papp M (1992) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 16:525–534. https://doi.org/10.1016/s0149-7634(05)80194-0

    Article  PubMed  CAS  Google Scholar 

  20. Zhang Y, Wang HB, Yang HX, Chen Q, Zhao L (2010) Content determination of monoamine neurotransmitter in different encephalic regions in rat by fluorospectrophotometry. J Northeast Agric Univ 41:93–96. https://doi.org/10.3788/gzxb20103904.0680

    Article  Google Scholar 

  21. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M (2006) Evaluation of outcomes with citalopram for depression using measurement based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40. https://doi.org/10.1176/appi.ajp.163.1.28

    Article  PubMed  Google Scholar 

  22. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905–1917. https://doi.org/10.1176/ajp.163.11.1905

    Article  PubMed  Google Scholar 

  23. Vollmayr B, Henn FA (2003) Stress models of depression. Clin Neurosci Res 3:245–251. https://doi.org/10.1016/S1566-2772(03)00086-0

    Article  Google Scholar 

  24. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902. https://doi.org/10.1038/nature07455

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Zhang F, Shao J, Tian J, Zhong Y, Ye L, Meng X, Liu Q, Wang H (2016) Antidepressant-like effects of LPM580153, a novel potent triple reuptake inhibitor. Sci Rep 6:24233. https://doi.org/10.1038/srep24233

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Arumugam V, John VS, Augustine N, Jacob T, Joy SM, Sen S, Sen T (2017) The impact of antidepressant treatment on brain-derived neurotrophic factor level: an evidence-based approach through systematic review and meta-analysis. Indian J Pharmacol 49:236–242. https://doi.org/10.4103/ijp.IJP_700_16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Castrén E, Rantamäki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70:289–297. https://doi.org/10.1002/dneu.20758

    Article  PubMed  CAS  Google Scholar 

  28. Castren E, Voikar V, Rantamaki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21. https://doi.org/10.1016/j.coph.2006.08.009

    Article  PubMed  CAS  Google Scholar 

  29. Kong SY, Li QF, Yang J, He L (2007) The effect of Butylphthalide on expression of NGF and BDNF in ischemia stroke tissue of rat cerebrum. Sichuan Da Xue Xue Bao (Medical Science Edition) 38:400–403

    CAS  Google Scholar 

  30. 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 475:91–95. https://doi.org/10.1038/nature10130

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M (2009) Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci 29:8688–8697. https://doi.org/10.1523/JNEUROSCI.6078-08.2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Spencer JL, Waters EM, Milner TA, Lee FS, McEwen BS (2010) BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.0915105107

    Article  PubMed  PubMed Central  Google Scholar 

  33. 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 329:959–964. https://doi.org/10.1126/science.1190287

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81560584).

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  1. Chunlin Chen and Hao Ma have equally contributed to this work.

Authors and Affiliations

  1. Chemistry and Biological Engineering Academy, Yichun University, Yichun, 336000, China

    Chunlin Chen & Zhifeng Fu

  2. Aesthetic Medical School, Yichun University, Yichun, 336000, China

    Hao Ma

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  1. Chunlin Chen
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  2. Hao Ma
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Correspondence to Chunlin Chen.

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Chen, C., Ma, H. & Fu, Z. Antidepressant-like Effect of 3-n-Butylphthalide in Rats Exposed to Chronic Unpredictable Mild Stress: Modulation of Brain-Derived Neurotrophic Factor Level and mTOR Activation in Cortex. Neurochem Res 46, 3075–3084 (2021). https://doi.org/10.1007/s11064-021-03397-9

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