Antidepressant Effect of Crocus sativus Aqueous Extract and its Effect on CREB, BDNF, and VGF Transcript and Protein Levels in Rat Hippocampus

T. Ghasemi; K. Abnous; F. Vahdati; S. Mehri; B. M. Razavi; H. Hosseinzadeh

doi:10.1055/s-0034-1371876

Drug Research, Table of Contents

Drug Res (Stuttg) 2015; 65(07): 337-343
DOI: 10.1055/s-0034-1371876

Original Article

Antidepressant Effect of Crocus sativus Aqueous Extract and its Effect on CREB, BDNF, and VGF Transcript and Protein Levels in Rat Hippocampus

Authors

T. Ghasemi

¹Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
K. Abnous

²Pharmaceutical Research Center, Department of Medicinal Chemistry, Mashhad University of Medical Sciences, Mashhad, Iran
F. Vahdati

¹Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
S. Mehri

³Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
B. M. Razavi

⁴Targeted Drug Delivery Research Center, Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
H. Hosseinzadeh

³Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Crocus sativus L., commonly known as saffron, is a perennial stemless herb in Iridaceae family. It has been used in traditional medicine as well as in modern pharmacological studies for variety of conditions including depression. Recent studies have suggested brain-derived neurotrophic factor (BDNF), VGF Neuropeptide, Cyclic-AMP Response Element Binding Protein (CREB) and phospho-CREB (p-CREB) may play roles in depression. In this research the molecular mechanism of antidepressant effect of aqueous extract of saffron and its effect on the levels of BDNF, VGF, CREB and p-CREB in rat hippocampus, were investigated. The aqueous extract of saffron (40, 80 and 160 mg/kg/day) and imipramine 10 mg/kg/day were injected intraperitoneally (i.p.) for 21 days to rats. The FST (forced swimming test) was performed on the days 1^st and 21^st. The protein expression and transcript levels of BDNF, VGF CREB and phospho-CREB in rat hippocampus, were evaluated using western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The results of FST showed that saffron reduced the immobility time. The protein levels of BDNF, CREB and p-CREB were significantly increased in saffron treated rats. VGF protein expression was also increased, but not significantly. The transcript levels of BDNF significantly increased. No significant changes in CREB and VGF transcript levels were observed. It was concluded that aqueous extract of saffron has antidepressant effects and the mechanism of its antidepressant effect may be due to increasing the levels of BDNF, VGF, CREB and P-CREB in rat hippocampus.

Key words

saffron - Crocus sativus - antidepressant - forced swimming test - Western blot - BDNF - VGF - CREB - P-CREB

Full Text

References

References
1 Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006; 7: 137-151
2 Haenisch B, Bönisch H. Depression and antidepressants: Insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Pharmacol Ther 2011; 129: 352-368
3 Hisaoka K, Maeda N, Tsuchioka M et al. Antidepressants induce acute CREB phosphorylation and CRE-mediated gene expression in glial cells: a possible contribution to GDNF production. Brain Res 2008; 1196: 53-58
4 Aydemir O, Devecia A, Tanelib 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: 261-265
5 Thakker-varia S, Alder J. Neuropeptides in depression: role of VGF. Behav Brain Res 2009; 197: 262-278
6 Bathaie S, Mousavi S. New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nut 2010; 50: 761-786
7 Rezaee R, Hosseinzadeh H. Safranal: from an aromatic natural product to a rewarding pharmacological agent. Iran J Basic Med Sci 2013; 16: 12-26
8 Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: A comprehensive review. Food Chem Toxicol 2014; 64: 65-80
9 Hosseinzadeh H, Nassiri-Asl M. Avicenna’s (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): A Review. Phytother Res 2013; 27: 475-483
10 Schmidt M, Betti G, Hensel A. Saffron in phytotherapy: pharmacology and clinical uses. Wien Med Wochenschr 2007; 157: 315-319
11 Fernández J. Anticancer properties of saffron, Crocus sativus Linn. Advances in Phytomedicine 2006; 2: 313-330
12 Hosseinzadeh H, Khosravan V. Anticonvulsant effects of aqueous and ethanolic extracts of Crocus sativus L. stigmas in mice. Arch Iran Med 2002; 44-47
13 Hosseinzadeh H, Younesi MH. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 2002; 2: 7
14 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 2010; 5: 419-424
15 Hosseinzadeh H, Ghenaati J. Evaluation of the antitussive effect of stigma and petals of saffron (Crocus sativus) and its components, safranal and crocin in guinea pigs. Fitoterapia 2006; 77: 446-448
16 Hariri A, Moallem S, Mahmoudi M et al. The effect of crocin and safranal, constituents of saffron, against subacute effect of diazinon on hematological and genotoxicity indices in rats. Phytomedicine 2011; 18: 499-504
17 Lari P, Abnous K, Imenshahidi M et al. Evaluation of diazinon-induced hepatotoxicity and protective effects of crocin. Toxicol Ind Health. 2013 2013 [Epub ahead of print] doi: 10.1177/0748233713475519
18 Razavi BM, Hosseinzadeh H, Movassaghi AR et al. Protective effect of crocin on diazinon induced cardiotoxicity in subcronic exposure. Chem Biol Interact 2013; 203: 547-555
19 Razavi M, Hosseinzadeh H, Abnous Kh et al. Crocin restores hypotensive effect of subchronic administration of diazinon in rats. Iran J Basic Med Sci 2013; 16: 64-72
20 Mehri S, Abnous K, Mousavi S et al. Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 2012; 32: 227-235
21 Sheng L, Qian Z, Zheng S et al. Mechanism of hypolipidemic effect of crocin in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 2006; 543: 116-122
22 Imenshahidi M, Hosseinzadeh H, Javadpour Y. Hypotensive effect of aqueous saffron extract (Crocus sativus l.) and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother Res 2010; 24: 990-994
23 Hosseinzadeh H, Sadeghnia H, Ghaeni F et al. 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: 381-386
24 Wang JW, Dranovsky A, Hen R. The when and where of BDNF and the antidepressant response. Biol Psychiatry 2008; 63: 640-641
25 Akhondzadeh Sh, Fallah-Pour H, Afkham KH et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: A pilot double-blind randomized trial. BMC complem Altern Med 2004; 4: 12-17
26 Hosseinzadeh H, Karimi GH, Niapoor M. Antidepressant effect of Crocus sativus L. Stigma extracts and their constituents, crocin and safranal, in Mice. J Med Plants 2004; 3: 48-58
27 Porsolt DR, Le PM, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977; 266: 730
28 Hill MN, Karacabeyli ES, Gorzalka BB. Estrogen recruits the endocannabinoid system to modulate emotionality. Psychoneuroendocrinol 2007; 32: 350-357
29 Porsolt DR, Anton G, Blavet N et al. Behavioral despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978; 47: 379-391
30 Nakamura K, Tanaka Y. Antidepressant-like effects of aniracetam in aged rats and its mode of action. Psychopharmacol 2001; 158: 205-212
31 Karimi GR, Hosseinzadeh H, Khaleghpanah P. Study of antidepressant effects of aqueous and ethanolic extracts of Crocus sativus in mice. Iran J Basic Med Sci 2002; 4
32 Gronli J, Bramham C, Murison R et al. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav 2006; 85: 842-849
33 Yulug B, Ozan E, Saffet Gonul A et al. Brain-derived neurotrophic factor, stress and depression: A minireview. Brain Res Bull 2009; 78: 267-269
34 Witkin JM, Li X. New Approaches to the Pharmacological Management of Major Depressive Disorder. Adv Pharmacol 2009; 57: 347-379
35 Allaman I, Fiumelli H, Magistretti PJ et al. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacol 2011; 216: 75-84
36 Carlezon WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci 2005; 28: 437-445
37 Castren E. Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol 2004; 4: 58-64