Skip to main content
SpringerLink
Log in

Derivatives of 3, 4, 5-Trimethoxycinnamic Acid Ameliorate Stress-Induced Anxiety in Mice and Rats

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Stress is an overwhelming problem associated with neuronal damage leading to anxiety and depression. The compound 3, 4, 5-trimethoxycinnamic acid (TMCA) has shown anti-stress effects; however, its derivatives remained unknown for their anxiolytic properties. Here, therefore, we investigated derivatives of TMCA (dTMCA) for their anxiolytic effects using immobilization and electric shock-induced stress in rats. Derivatives of TMCA ameliorated anxiety in mice and rats revealed by extended period of time spent in the open arms of elevated plus maze. Stress-mediated repression of tyrosine hydroxylase (TH) protein expression in the amygdala regions of rat brain and dopamine levels in the PC12 cells was restored by two selected derivatives (TMCA#5 and TMCA#9). Unlike TH expression, stress-induced protein expression of phospho-extracellular signal-regulated kinase (pERK) was unaffected by both derivatives in rats. Given the preferential inhibitory activity of dTMCA on dopamine and serotonin receptors, serotonergic road map of cellular signaling could be their target for anxiolytic effects. Thus, dTMCA would be promising agents to prevent neuronal damage associated with rampant stressful conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Jung JC, Moon S, Min D, Park WK, Jung M, Oh S (2013) Synthesis and evaluation of a series of 3,4,5-trimethoxycinnamic acid derivatives as potential antinarcotic agents. Chem Biol Drug Des 81(3):389–398. https://doi.org/10.1111/cbdd.12087

    Article  CAS  PubMed  Google Scholar 

  2. Leem YH, Oh S (2015) 3,4,5-Trimethoxycinnamin acid ameliorates restraint stress-induced anxiety and depression. Neurosci Lett 585:54–59

    Article  CAS  PubMed  Google Scholar 

  3. Etievant A, Betry C, Haddjeri N (2010) Partial dopamine D2/serotonin 5-HT1A receptor agonists as new therapeutic agents. Open Neuropsychopharmacol J 3

  4. Mravec B, Vargovic P, Filipcik P, Novak M, Kvetnansky R (2015) Effect of a single and repeated stress exposure on gene expression of catecholamine biosynthetic enzymes in brainstem catecholaminergic cell groups in rats. Eur J Neurosci 42(2):1872–1886. https://doi.org/10.1111/ejn.12955

    Article  PubMed  Google Scholar 

  5. Krzyzowska M, Swiatek W, Fijalkowska B, Niemialtowski M, Schollenberger A (2014) The role of map kinases in immune response. Med J Cell Biol 2(3):125–138. https://doi.org/10.2478/v10052-010-0007-5

    Article  Google Scholar 

  6. Shen CP, Tsimberg Y, Salvadore C, Meller E (2004) Activation of Erk and JNK MAPK pathways by acute swim stress in rat brain regions. BMC Neurosci 5:36. https://doi.org/10.1186/1471-2202-5-36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sananbenesi F, Fischer A, Schrick C, Spiess J, Radulovic J (2003) Mitogen-activated protein kinase signaling in the hippocampus and its modulation by corticotropin-releasing factor receptor 2: a possible link between stress and fear memory. J Neurosci 23(36):11436–11443. https://doi.org/10.1523/jneurosci.23-36-11436.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Meltser I, Tahera Y, Canlon B (2009) Glucocorticoid receptor and mitogen-activated protein kinase activity after restraint stress and acoustic trauma. J Neurotrauma 26(10):1835–1845. https://doi.org/10.1089/neu.2008.0874

    Article  PubMed  Google Scholar 

  9. Gilad GM, McCarty R (1981) Difference in choline acetyltransferase but similarities in catecholamine biosynthetic enzymes in brains of two rat strains differing in their response to stress. Brain Res 206(1):239–243. https://doi.org/10.1016/0006-8993(81)90124-4

    Article  CAS  PubMed  Google Scholar 

  10. Lee CI, Han JY, Hong JT, Oh KW (2013) 3,4,5-Trimethoxycinnamic acid (TMCA), one of the constituents of Polygalae Radix enhances pentobarbital-induced sleeping behaviors via GABAAergic systems in mice. Arch Pharm Res 36(10):1244–1251. https://doi.org/10.1007/s12272-013-0167-6

    Article  CAS  PubMed  Google Scholar 

  11. Gupta D, Prabhakar V, Radhakrishnan M (2016) 5HT3 receptors: target for new antidepressant drugs. Neurosci Biobehav Rev 64:311–325

    Article  CAS  PubMed  Google Scholar 

  12. Jung JC, Moon S, Min D, Park WK, Jung M, Oh S (2013) Synthesis and evaluation of a series of 3,4,5-trimethoxycinnamic acid derivatives as potential antinarcotic agents. Chem Biol Drug Des 81(3):389–398

    Article  CAS  PubMed  Google Scholar 

  13. Moreno-Martínez S, Tendilla-Beltrán H, Sandoval V, Flores G, Terrón JA (2022) Chronic restraint stress induces anxiety-like behavior and remodeling of dendritic spines in the central nucleus of the amygdala. Behav Brain Res 416:113523. https://doi.org/10.1016/j.bbr.2021.113523

    Article  PubMed  Google Scholar 

  14. Lim H, Jang S, Lee Y, Moon S, Kim J, Oh S (2012) Enhancement of anxiety and modulation of TH and pERK expressions in amygdala by repeated injections of corticosterone. Biomol Ther (Seoul) 20(4):418–424. https://doi.org/10.4062/biomolther.2012.20.4.418

    Article  CAS  PubMed  Google Scholar 

  15. Jung JC, Min D, Kim H, Jang S, Lee Y, Park W, Khan IA, Moon HI, Jung M, Oh S (2010) Design, synthesis, and biological evaluation of 3,4,5-trimethoxyphenyl acrylamides as antinarcotic agents. J Enzyme Inhib Med Chem 25(1):38–43. https://doi.org/10.3109/14756360902932784

    Article  CAS  PubMed  Google Scholar 

  16. Moon SH (2012) Antinarcotic and anxiolytic effects of 3,4,5-trimethoxycinnamic acid and its analogues. The Graduate School Ewha Womans Universrity, Seoul, Republic of Korea

    Google Scholar 

  17. Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol Sci 16(2):33–36

    Article  CAS  PubMed  Google Scholar 

  18. Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, Yoneyama M, Ogita K, Yoneda Y, Nabeshima T, Nagai T, Yamada K (2010) Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. J Neurochem 114(6):1840–1851. https://doi.org/10.1111/j.1471-4159.2010.06893.x

    Article  CAS  PubMed  Google Scholar 

  19. de Lores R, Arnaiz G, Antonelli MC (2016) In search of concomitant alterations of dopaminergic and neurotensinergic systems in stress conditions. Neurochem Res 41(1-2):423–430

    Article  Google Scholar 

  20. Costa AP, Lopes MW, Rieger DK, Barbosa SG, Goncalves FM, Xikota JC, Walz R, Leal RB (2016) Differential activation of mitogen-activated protein kinases, ERK 1/2, p38(MAPK) and JNK p54/p46 during postnatal development of rat hippocampus. Neurochem Res 41(5):1160–1169

    Article  CAS  PubMed  Google Scholar 

  21. Ferreira R, Nobre MJ (2014) Conditioned fear in low- and high-anxious rats is differentially regulated by cortical subcortical and midbrain 5-HT(1A) receptors. Neuroscience 268:159–168

    Article  CAS  PubMed  Google Scholar 

  22. Hjorth S (2016) Looking back (and in)to the future: a personal reflection on 'Serotonin autoreceptor function and antidepressant drug action' (Hjorth et al., 2000). J Psychopharmacol 10:1129–1136

    Article  Google Scholar 

  23. Zhao Z, Bai Y, Xie J, Chen X, He X, Sun Y, Bai Y, Zhang Y, Wu S, Zheng X (2019) Excavating precursors from the traditional Chinese herb Polygala tenuifolia and Gastrodia elata: synthesis, anticonvulsant activity evaluation of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives. Bioorg Chem 88:102832. https://doi.org/10.1016/j.bioorg.2019.03.006

    Article  CAS  PubMed  Google Scholar 

  24. De Paula BB, Leite-Panissi CR (2016) Distinct effect of 5-HT1A and 5-HT2A receptors in the medial nucleus of the amygdala on tonic immobility behavior. Brain Res 15:152–158

    Article  Google Scholar 

  25. Vollenweider FX, Vontobel P, Hell D, Leenders KL (1999) 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride. Neuropsychopharmacology 20(5):424–433. https://doi.org/10.1016/s0893-133x(98)00108-0

    Article  CAS  PubMed  Google Scholar 

  26. Lorrain DS, Matuszewich L, Hull EM (1998) 8-OH-DPAT influences extracellular levels of serotonin and dopamine in the medial preoptic area of male rats. Brain Res 790(1-2):217–223. https://doi.org/10.1016/s0006-8993(98)00065-1

    Article  CAS  PubMed  Google Scholar 

  27. Blum M, McEwen BS, Roberts JL (1987) Transcriptional analysis of tyrosine hydroxylase gene expression in the tuberoinfundibular dopaminergic neurons of the rat arcuate nucleus after estrogen treatment. J Biol Chem 262(2):817–821

    Article  CAS  PubMed  Google Scholar 

  28. Johnson EA, Tsai CE, Shahan YH, Azzaro AJ (1993) Serotonin 5-HT1A receptors mediate inhibition of tyrosine hydroxylation in rat striatum. J Pharmacol Exp Ther 266(1):133–141

    CAS  PubMed  Google Scholar 

  29. Cai CY, Wu HY, Luo CX, Zhu DY, Zhang Y, Zhou QG, Zhang J (2019) Extracellular regulated protein kinaseis critical for the role of 5-HT1a receptor in modulating nNOS expression and anxiety-related behaviors. Behav Brain Res 357:88–97. https://doi.org/10.1016/j.bbr.2017.12.017

    Article  CAS  PubMed  Google Scholar 

  30. Qiu Y, Wang Y, Wang X, Wang C, Xia ZY (2018) Role of the hippocampal 5-HT1A receptor-mediated cAMP/PKA signalling pathway in sevoflurane-induced cognitivedysfunction in aged rats. J Int Med Res 46(3):1073–1085. https://doi.org/10.1177/0300060517744037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lewis-Tuffin LJ, Quinn PG, Chikaraishi DM (2004) Tyrosine hydroxylase transcription depends primarily on cAMP response element activity, regardless of the type of inducing stimulus. Mol Cell Neurosci 25(3):536–547. https://doi.org/10.1016/j.mcn.2003.10.010

    Article  CAS  PubMed  Google Scholar 

  32. Kravets JL, Reyes BA, Unterwald EM, Van Bockstaele EJ (2015) Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry. Brain Struct Funct 220(1):541–558

    Article  CAS  PubMed  Google Scholar 

  33. Samad N, Batool F, Haleem DJ (2007) Neurochemical and behavioral effects of 8-OH-DPAT following exposure to restraint stress in rats. Pharmacol Rep 59(2):173–180

    CAS  PubMed  Google Scholar 

  34. Goto T, Toyoda A (2015) A mouse model of subchronic and mild social defeat stress for understanding stress-induced behavioral and physiological deficits. J Vis Exp 24(105):52973

    Google Scholar 

Download references

Funding

This work was supported by the Ministry of Food and Drug Safety (20182MFDS422, 20182MFDS425, 22214MFDS252), a National Research Foundation of Korea (NRF) grant funded by the Korea government, Ministry of Science (MEST; MRC 2010-0029355) (MISIT; No. MRC, 2017R1A5A2015541), and “Regional Innovation Strategy (RIS)” through the NRF funded by the Ministry of Education (MOE) (2021RIS-001).

Author information

Author notes

  1. Eunchong Hong, Hyun Kyu Min, Heena Lim, and Sun Mi Gu contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Chungbuk National University, Cheongju-si, Chungbuk, 28160, Korea

    Eunchong Hong, Hyun Kyu Min, Sun Mi Gu, Abdulaziz Jabborov & Jaesuk Yun

  2. Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul, 07804, Korea

    Heena Lim, Taddesse Yayeh, Mijin Kim, Jae-Chul Jung & Seikwan Oh

  3. Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea

    Woo-Kyu Park

Authors
  1. Eunchong Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun Kyu Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heena Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sun Mi Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdulaziz Jabborov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taddesse Yayeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mijin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Woo-Kyu Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jae-Chul Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jaesuk Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seikwan Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Material preparation, data collection, analysis, and writing — review and editing were performed by Eunchong Hong. Material preparation, data collection, analysis, and writhing — original draft were performed by Hyun Kyu Min. Data curation, visualization, writhing — original draft, and writing — review and editing were performed by Heena Lim and Sun Mi Gu. Material preparation, data collection, and analysis were performed by Abdulaziz Jabborov, Taddesse Yayeh, Mijin Kim, Woo-Kyu Park, and Jae-Chul Jung. Conceptualization, data curation, project administration, supervision, resources, and writing — review and editing were performed by Jaesuk Yun and Seikwan Oh. All authors proofread the final manuscript.

Corresponding authors

Correspondence to Jaesuk Yun or Seikwan Oh.

Ethics declarations

Ethics Approval

The study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments based on the guidelines approved by the Animal Care and Committee of Ewha Womans University and Chungbuk National University (CBNUA-436-12-02).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 206 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hong, E., Min, H.K., Lim, H. et al. Derivatives of 3, 4, 5-Trimethoxycinnamic Acid Ameliorate Stress-Induced Anxiety in Mice and Rats. Mol Neurobiol 60, 2737–2748 (2023). https://doi.org/10.1007/s12035-023-03240-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03240-y

Keywords

Search

Navigation