Saffron (Crocus sativus) aqueous extract reverses the hypothalamus-pituitary-adrenal axis activity in rat model of post-traumatic stress disorder

Abstract

Crocus sativus L., Iridaceae, has been used worldwide in traditional medicinefor treatment ofsome neurological disorderssuch as depression. Post-traumatic stress disorder is a mental disorder developed in peoplewho experience stressful events. Since stress has been proposed to cause the hypothalamic-pituitary-adrenal axis malfunction in post-traumatic stress disorder patients, this study aimed at investigating the effect of saffron aqueous extract on hypothalamic-pituitary-adrenal axis activity in rats of post-traumatic stress disorder model. Here, Post-traumatic stress disorder animals received an acute electro foot shock; however, 5 min before the stress session, these animals received an intracerebral-ventricular (10 (xg/rat) infusion of either saffron aqueous extract or saline. Twenty one days later, they were re-exposedto the stress box withoutinducing stress, andthen were examined for their freezing behavior. The impact of stress and saffron aqueous extract on serum corticosterone, corticotrophin releasing hormone gene expression in hypothalamus and glucocorticoid receptor gene expression in pituitary gland werethen evaluated on day 28. Intra-cerebral-ventricular injection of saffron aqueous extract resulted in an increase in serum corticosterone level and reduced symptoms of freezing behavior, and corticotrophin releasing hormone and glucocorticoid receptor gene expression in post-traumatic stress disorder groups.Saffron administration could improve the symptoms of stress-induced post-traumatic stress disorder, possiblythrough the adjustment ofhypothalamic-pituitary-adrenal axis function.

References

  1. Asalgoo, S., Jahromi, G., Meftahi, G., Sahraei, H., 2015. Posttraumatic stress disorder (ptsd): mechanisms and possible treatments. Neurophysiology 47, 482–489.

    Article  CAS  Google Scholar 

  2. Asalgoo, S., Tat, M., Sahraei, H., Jahromi, G.P., 2017. The psychoactive agent crocin can regulate hypothalamic-pituitary-adrenal axis activity. Front. Neurosci. 11, https://doi.org/10.3389/fnins.2017.00668.

  3. Berger, F., Hensel, A., Nieber, K., 2011. Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices. Neuroscience 180, 238–247.

    Article  CAS  Google Scholar 

  4. Breslau, N., 2009. The epidemiology oftrauma, ptsd, and other posttrauma disorders. Trauma Violence Abus. 10, 198–210.

    Article  Google Scholar 

  5. Breslau, N., Kessler, R.C., Chilcoat, H.D., Schultz, LR., Davis, G.C., Andreski, P., 1998. Trauma and posttraumatic stress disorder in the community: The 1996 detroit area survey oftrauma. Arch. Gen. Psychiat. 55, 626–632.

    Article  CAS  Google Scholar 

  6. Carvalho, LA., Juruena, M.F., Papadopoulos, A.S., Poon, L., Kerwin, R., Cleare, A.J., Pariante, CM., 2008. Clomipramine invitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression. Neuropsychophar-macology 33, 3182–3189.

    Article  CAS  Google Scholar 

  7. Chen, J., Evans, A.N., Liu, Y., Honda, M., Saavedra, J.M., Aguilera, G., 2012. Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J. Neuroendocrinol. 24, 1055–1064.

    Article  CAS  Google Scholar 

  8. De Kloet, E.R., Vreugdenhil, E., Oitzl, M.S., Joe¨Ls, M., 1998. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301.

    PubMed  Google Scholar 

  9. Dunn, A.J., Swiergiel, A.H., 2008. The role ofcorticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur. J. Pharmacol. 583, 186–193.

    Article  CAS  Google Scholar 

  10. Ettehadi, H., Mojabi, S.N., Ranjbaran, M., Shams, J., Sahraei, H., Hedayati, M., Asefi, F., 2013. Aqueous extract of saffron (Crocus sativus) increases brain dopamine and glutamate concentrations in rats. J. Behav. Brain Sci. 3, https://doi.org/10.4236/jbbs.2013.33031.

  11. Gohari, A.R., Saeidnia, S., Mahmoodabadi, M.K., 2013. An overview on saffron, phytochemicals, and medicinal properties. Pharmacogn. Rev. 7, 61–66.

    Article  CAS  Google Scholar 

  12. Hadipour, M., Kaka, G., Bahrami, F., Meftahi, G.H., 2018. Crocin improved amyloid beta induced long-term potentiation and memory deficits in the hippocampal CA1 neurons in freely moving rats. Sinapse 72, e22026.

  13. Hashtjini, M.M., Jahromi, G.P., Sadr, S.S., Meftahi, G.H., Hatef, B., Javidnazar, D., 2018. Deep brain stimulation in a rat model of post-traumatic stress disorder modifies forebrain neuronal activity and serum corticosterone. Iran J, Basic Med, Sci. 21, 370–375.

    Google Scholar 

  14. Hooshmandi, Z., Rohani, A.H., Eidi, A., Fatahi, Z., Golmanesh, L., Sahraei, H., 2011. Reduction of metabolic and behavioral signs of acute stress in male wistar rats by saffron water extract and its constituent safranal. Pharm. Biol. 49, 947–954.

    Article  CAS  Google Scholar 

  15. Hosseinzadeh, H., Noraei, N.B., 2009. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother. Res. 23, 768–774.

    Article  CAS  Google Scholar 

  16. Howes, O.D., Mccutcheon, R., Owen, M.J., Murray, R.M., 2017. The role of genes, stress, and dopamine in the development of schizophrenia. Biol. Psychiat. 81, 9–20.

    Article  CAS  Google Scholar 

  17. Jacobson, L., 2005. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrin. Metab. Clin. 34, 271–292.

    Article  CAS  Google Scholar 

  18. Kar, N., 2011. Cognitive behavioral therapy forthe treatment of post-traumatic stress disorder: a review. Neuropsychiat. Dis. Treat. 7, 167–181.

    Article  Google Scholar 

  19. Kessler, R.C., 2000. Posttraumatic stress disorder: the burden to the individual and to society. J. Clin. Psychiatry 61 (Suppl 5), 4–12, discussion 13-4.

    PubMed  Google Scholar 

  20. Khazdair, M.R., Boskabady, M.H., Hosseini, M., Rezaee, R., Tsatsakis, A.M., 2015. The effects of Crocus sativus (saffron) and its constituents on nervous system: a review. Avicenna J. Phytomed. 5, 376–391.

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Kupfer, D.J., Kuhl, E.A., Regier, D.A., 2013. Dsm-5—the future arrived. Jama 309, 1691–1692.

    Article  CAS  Google Scholar 

  22. Lechtenberg, M., Schepmann, D., Niehues, M., Hellenbrand, N., Wünsch, B., Hensel, A., 2008a. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and σ1 (sigma-1) receptors. Planta Med. 74, 764–772.

    Article  CAS  Google Scholar 

  23. McEwen, B.S., Gould, E.A., Sakai, R.R., 1992. The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress. Brit. J. Psychiat., 18–23, Suppl.

    Google Scholar 

  24. McEwen, B.S., 2009. The brain is the central organ of stress and adaptation. Neuroimage 47, 911–913.

    Article  Google Scholar 

  25. Mikics, E., Baranyi, J., Haller, J., 2008. Rats exposed to traumatic stress bury unfamiliar objects - a novel measure of hyper-vigilance in ptsd models? Physiol. Behav. 94, 341–348.

    Article  CAS  Google Scholar 

  26. Mojabi, N.A., Imani, H., Riahi, S., Shajiei, H., Goshoni, H., Motahari, A., 2017. The role nmda receptors within the nucleus accumbens in acute stress in male wistar rats. Int. J. Advan. Biotechnol. Res. 8, 728–733.

    CAS  Google Scholar 

  27. Mokhtari Hashtjini, M., Pirzad Jahromi, G., Meftahi, G.H., Esmaeili, D., Javidnazar, D., 2018. Aqueous extract of saffron administration along with amygdala deep brain stimulation promoted alleviation of symptoms in post-traumatic stress disorder (PTSD) in rats. Avicenna J. Phytomed. 8, 358–369.

    PubMed  PubMed Central  Google Scholar 

  28. Moshiri, E., Basti, A.A., Noorbala, A.A., Jamshidi, A.H., Abbasi, S.H., Akhondzadeh, S., 2006. Crocus sativus L (petal) in the treatment of mild-to-moderate depression: a double-blind, randomized and placebo-controlled trial. Phytomedicine 13, 607–611.

    Article  Google Scholar 

  29. Paxinos, G., Watson, C., 2006. The rat brain in stereotaxic coordinates. Elsevier, Amsterdam, pp. 472.

    Google Scholar 

  30. Popoli, M., Yan, Z., Mcewen, B.S., Sanacora, G., 2012. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22–37.

    Article  CAS  Google Scholar 

  31. Sahraei, H., Fatahi, Z., Eidi, A., Haeri-Rohani, A., Hooshmandi, Z., Shekarforoush, S., Tavalaei, S.A., 2012a. Inhibiting post traumatic stress disorder (PTSD) induced by electric shock using ethanol extract of saffron in rats. J. Biol. Res. Thessalon. 18, 320–327.

    Google Scholar 

  32. Sahraei, H., Fatahi, Z., Rohani, A., Eidi, A., Hooshmandi, Z., Tavalaei, S., 2012b. Ethanolic extract of saffron and its constituent crocin diminish stress-induced metabolic signs and alterations of dopamine-related behaviours in rats. Int. Res. J. Pharm. Pharmacol. 2, 165–173.

    Google Scholar 

  33. Tzschentke, T.M., 2007. Review on cpp: measuring reward with the conditioned place preference (cpp) paradigm: Update of the last decade. Addict. Biol. 12, 227–462.

    Article  CAS  Google Scholar 

  34. Vale, W., Rivier, C., Brown, M.R., Spiess, J., Koob, G., Swanson, L., Bilezikjian, L., Bloom, F., Rivier, J., 2013. Chemical and biological characterization of corticotropin releasing factor. Recent Prog. Horm. Res. 39, 245–270.

    Google Scholar 

  35. Winer, J., Jung, C.K.S., Shackel, I., Williams, P.M., 1999. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytesin vitro. Anal. biochem. 270, 41–49.

    Article  CAS  Google Scholar 

  36. Yehuda, R., 2002. Current status of cortisol findings in post-traumatic stress disorder. Psychiat. Clin. N. Am. 25, 341–368.

    Article  Google Scholar 

  37. Yehuda, R., Golier, JA., Kaufman, S., 2005. Circadian rhythm of salivary cortisol in holocaust survivors with and without ptsd. Am. J. Psychiat. 162, 998–1000.

    Article  Google Scholar 

  38. Yuen, E.Y., Wei, J., Liu, W., Zhong, P., Li, X., Yan, Z., 2012. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 73, 962–977.

    Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Gila Pirzad Jahromi.

Additional information

Author contributions

SA: experimental work; GPJ: design of the study, experimental work, drafting of the paper, major revisions and final approval for publication; BH: statistical analysis, scientific writing and final approval for publication; HS: design of the study and extract preparation; JRS: experimental work; SSS: design of the study; GHM: scientific writing and revision.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Asalgoo, S., Jahromi, G.P., Hatef, B. et al. Saffron (Crocus sativus) aqueous extract reverses the hypothalamus-pituitary-adrenal axis activity in rat model of post-traumatic stress disorder. Rev. Bras. Farmacogn. 29, 470–476 (2019). https://doi.org/10.1016/j.bjp.2019.01.011

Download citation

Keywords

  • Post traumatic stress disorder
  • Saffron aqueous extract
  • Corticosterone
  • corticotrophin releasing hormone
  • glucocorticoid receptor
  • freezing behavior