Antidepressant effects of aqueous extract of saffron and its effects on CREB, P-CREB, BDNF, and VGF proteins in rat cerebellum

  • Asrari, Najmeh (School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Yazdian-Robati, Rezvan (Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Abnous, Khalil (Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Razavi, BiBi Marjan (Targeted Drug Delivery Research Center, Department of Pharmacology and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Rashednia, Mrazieh (Department of Toxicology and pharmacology, School of Pharmacy, International branch, Shiraz University of Medical Sciences) ;
  • Hasani, Faezeh Vahdati (School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Hosseinzadeh, Hossein
  • Received : 2017.05.10
  • Accepted : 2018.02.26
  • Published : 2018.03.31


Objective: The role of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide has been proved in antidepressant activity of long term saffron administration in the rat hippocampus. In this study we evaluated the role of these proteins in antidepressant activity of saffron in long term administration in the rat cerebellum. Methods: Saffron aqueous extract (40 and 80 mg/kg/day) and imipramine (10 mg/kg/day) were administered intraperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were separated. The protein levels of BDNF, VGF, CREB and P- CREB in the rat cerebellum were evaluated using western blot analysis. Results: Saffron aqueous extract (80mg/kg/day) caused significant increase in protein level of P-CREB in long term treatment in the rat cerebellum. The increases in the protein levels of VGF, CREB and BDNF were not significant. Conclusion: In summary, our results showed that antidepressant effect of saffron in rat cerebellum might be due to the enhanced phosphorylation of CREB.


  1. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nature Rev Neurosci. 2006;7(2):137-51.
  2. Haenisch B, Bonisch H. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Pharmacol Ther. 2011;129(3):352-68.
  3. Penga J, Liua J, Nieb B, Li Y, Shanb B, Wangc G, et al. Cerebral and cerebellar gray matter reduction in first-episode patients with major depressive disorder: A voxel-based morphometry study. Eur J Radiol. 2011;80:395-9.
  4. Zeng L, Liu L, Liu Y, Shen H, Li Y, Hu D. Antidepressant Treatment Normalizes White Matter Volume in Patients with Major Depression. Plos One. 2012;7(8):e44248.
  5. Yulug B, Ozan E, Gonul AS, Kilic E. Brain-derived neurotrophic factor, stress and depression: a minireview. Brain Res Bull. 2009;78(6):267-9.
  6. Sarris J, Panossian A, Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol. 2011;21(12):841-60.
  7. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci. 1996;16(7):2365-72.
  8. Gass P, Riva MA. CREB, neurogenesis and depression. BioEssays. 2007;29(10):957-61.
  9. Thakker-Varia S, Alder J. Neuropeptides in depression: role of VGF. Behav Brain Res. 2009;197(2):262-78.
  10. Hosseinzadeh H, Nassiri-Asl M. Avicenna's (Ibn Sina) the canon of medicine and saffron (Crocus sativus): a review. Phytother Res. 2013;27(4):475-83.
  11. Mollazadeh H, Emami SA, Hosseinzadeh H. Razi's Al-Hawi and saffron (Crocus sativus): a review. Iran J Basic Med Sci. 2015;18(12):1153-6.
  12. Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical applications of saffron (Crocus sativus) and its constituents: a review. Drug Res. 2015;65(6):287-95.
  13. Hosseinzadeh H, Shamsaie F, Mehri S. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituents, crocin and safranal. Pharmacogn Mag. 2009;5(20):419-24.
  14. Hosseinzadeh H, Karimi G, Niapoor M. Antidepressant effect of Crocus sativus L. stigma extracts and their constituents, crocin and safranal, in mice. Acta Hort. 2004;650: 435-445.
  15. Behravan J, Hosseinzadeh H, Rastgoo A, Mohamad ali pour malekashah O. Hessani M. Evaluation of the cytotoxic activity of crocin and safranal using potato disc and brine shrimp assays. Physiol Pharmacol. 2010;13(4):397-403.
  16. Rastgoo M, Hosseinzadeh H, Alavizadeh H, Abbasi A, Ayati Z, Jaafari MR. Antitumor activity of PEGylated nanoliposomes containing crocin in mice bearing C26 colon carcinoma. Planta Med. 2013;79(6): 447-451.
  17. Hosseinzadeh H, Sadeghnia, H.R. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: Involvement of GABAergic and opioids systems. Phytomedicine. 2007;14(4): 256-262.
  18. Hosseinzadeh H, Talebzadeh F. Anticonvulsant evaluation of safranal and crocin from Crocus sativus in mice. Fitoterapia. 2005;76(7-8): 722-724.
  19. Sadeghnia HR, Cortez MA, Liu D, Hosseinzadeh H, Snead CO. Antiabsence effects of safranal in acute experimental seizure models: EEG and autoradiography. J Pharm Pharm Sci. 2008;11(3):1-14.
  20. Hosseinzadeh H, Ziaei T. Effects of Crocus sativus stigma extract and its constituents, crocin and safranal, on intact memory and scopolamine-induced learning deficits in rats performing the Morris water maze task. J Med Plants. 2006; 5 (19): 40-50.
  21. Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res. 2012;26(3):381-6.
  22. Hosseinzadeh, H., Jahanian, Z. Effect of Crocus sativus L. (saffron) stigma and its constituents, crocin and safranal, on morphine withdrawal syndrome in mice. Phytother Res. 2010; 24 (5):726-730
  23. Hosseinzadeh H, Shariaty VM. Anti-nociceptive effect of safranal, a constituent of Crocus sativus (saffron), in mice. Pharmacologyonline, 2007; 2: 498-503.
  24. Amin B., Hosseinzadeh H. Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L., and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats. Fitoterapia. 2012;83(5):888-895.
  25. Golmohammadzadeh S, Jaafari MR, Hosseinzadeh H. Does saffron have antisolar and moisturizing effects? Iran J Pharm Res. 2010;9(2):133-140.
  26. Golmohammadzadeh S, Imani F, Hosseinzadeh H, Jaafari MR. Preparation, characterization and evaluation of sun protective and moisturizing effects of nanoliposomes containing safranal. Iran J Basic Med Sci. 2011;14(6): 521-533.
  27. Mehdizadeh R, Parizadeh MR, Khooei AR, Mehri S, Hosseinzadeh H. Cardioprotective effect of saffron extract and safranal in isoproterenol-induced myocardial infarction in wistar rats. IJBMS. 2013;16(1):56-63.
  28. Razavi BM, Hosseinzadeh H, Movassaghi AR, Imenshahidi M, Abnous K. Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure.Chem-Bio Interact. 2013a 203 (3): 547-555.
  29. Razavi M, Hosseinzadeh H, Abnous K, Motamedshariaty VS, Imenshahidi M. Crocin restores hypotensive effect of subchronic administration of diazinon in rats. Iran J Basic Med Sci. 2013b;16(1): 64-72.
  30. Lari P, Abnous K, Imenshahidi M, Rashedinia M, Razavi M, Hosseinzadeh H. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin. Toxicol Indust Health, 2015;31(4): 367-376.
  31. Nassiri-Asl M, Hosseinzadeh H. Neuropharmacology Effects of Saffron (Crocus sativus) and Its Active Constituents. Bioactive Nutraceuticals and Dietary Supple-ments in Neurological and Brain Disease. Prevention and Therapy, 2015;29.39
  32. Dorri SA, Hosseinzadeh H, Abnous K, Hasani FV, Robati RY, Razavi BM. Involvement of brain-derived neurotrophic factor (BDNF) on malathion induced depressive-like behavior in subacute exposure and protective effects of crocin. Iran J Basic Med Sci, 2015;18(10): 958-86.
  33. Razavi BM, Hosseinzadeh H. Saffron as an antidote or a protective agent against natural and chemical toxicities. DARU, J Pharm Sci. 2015;23(1): 112.
  34. Razavi BM, Hosseinzadeh H. Saffron: a promising natural medicine in the treatment of metabolic syndrome. J Sci Food Agric. 2017;97(6):1679-1685.
  35. Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial. BMC Complement Altern Med. 2004;4(1):12.
  36. Vahdati Hassani F, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. DARU, J Pharm Sci. 2014; 22(1):16.
  37. Ghasemi T, Abnous K, Vahdati F, Mehri S, Razavi B, Hosseinzadeh H. Antidepressant effect of Crocus sativus aqueous extract and its effect on CREB, BDNF, and VGF transcript and protein levels in Rat hippocampus. Drug Res (Stuttq). 2015;65(7):337-43.
  38. Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(2):261-5.
  39. Blendy JA. The Role of CREB in Depression and Antidepressant Treatment. Biol Psychiatry. 2006;59(12):1144-50.
  40. Laifenfeld D, Karry R, Grauer E, Klein E, Ben-Shachar D. Antidepressants and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. Neurobiol Dis. 2005;20(2):432-41.
  41. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, Latoussakis V, Kanellopoulos D, Klimstra S, et al. Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry. 2008;165(2):238-44.