Aqueous extract of saffron administration along with amygdala deep brain stimulation promoted alleviation of symptoms in post-traumatic stress disorder (PTSD) in rats

Document Type: Original Research Article


1 Neuroscience Research Centre, Baqiyatallah University of Medical Sciences, Tehran, Iran

2 Applied Microbiology Research Center, and Microbiology Department, Baqiyatallah University of Medical Sciences, Tehran, Iran

3 Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran


Objective: Post-traumatic stress disorder (PTSD) as one of the most devastating kinds of anxiety disorders, is the consequence of a traumatic event. Crocus sativus L., commonly known as saffron have been traditionally used for treatment of stress and anxiety. In this study, we evaluated the effects of peripheral administration of saffron, along with deep brain stimulation (DBS) in a post-traumatic stress disorder (PTSD) model caused by contextual fear conditioning (electrical foot shock chamber) in male Wistar rats.
Materials and Methods: rats (220-250 g) were divided into 7 groups (n=8) and underwent stereotactic surgery for implantation of the electrodes in the right-baso lateral of the amygdala (BLA). After 7 days, some animals received the foot shock, followed by another 7-day treatment (DBS treatment or combination treatment by saffron 5 mg/kg (i.p)) then freezing behavior as a predicted response in the absence of the foot shock (re-exposure time) and general anxiety were measured using elevated plus maze test. Serum corticosterone level and amygdala c-Fos protein expression were assessed using ELISA and Western blot analysis, respectively.
Results: DBS treatment and the combination therapy of saffron (5 mg/kg (I.P)) with DBS significantly (p<0.001) increased serum corticosterone levels. Also both treatments could significantly (p<0.001) reduce c-Fos protein expression and freezing behaviors time. However, DBS treatment had no effect on the general anxiety in rats with PTSD. On the other hand, combination therapy significantly (p<0.001) reduced anxiety behavior in rats with PTSD.
Conclusion: These results might show the potential of this combination therapy for treatment of treatment-resistant PTSD patients.


Main Subjects

Calleja-Castillo JM, De La Cruz-Aguilera DL, Manjarrez J, Velasco-Velázquez MA, Morales-Espinoza G, Moreno-Aguilar J, et al. 2013.Chronic deep brain stimulation of the hypothalamic nucleus in Wistar rats alters circulatory levels of corticosterone and proinflammatory cytokines. Clin Dev Immunol, 2013.

Cordero MI, Venero C, Kruyt ND, Sandi C .2003. Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats: Evidence for a role of corticosterone. Horm Behav, 44: 338-345.

De Kloet C, Vermetten E, Geuze E, Kavelaars A, Heijnen C, Westenberg H. 2006. Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res, 40:550-567.

De Koning PP, Figee M, Endert E, Storosum JG, Fliers E, Denys D. 2013. Deep brain stimulation for obsessive–compulsive disorder is associated with cortisol changes. Psychoneuroendocrinology, 38:1455-1459.

Delgado MR, Olsson A, Phelps EA. 2006. Extending animal models of fear conditioning to humans. Biol Psychol, 73:39-48.

Frances Davies M, Tsui J, Flannery JA, Li X, DeLorey TM, Hoffman BB. 2003. Activation of [alpha]2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala. Neuropsychopharmacology, 29:229-239

Franzini A, Broggi G, Cordella R, Dones I, Messina G. 2013. Deep-brain stimulation for aggressive and disruptive behavior. World Neurosurg, 80:S29 e11-4.

Georgiadou G, Tarantilis P, Pitsikas N. 2012. Effects of the active constituents of Crocus Sativus L., crocins, in an animal model of obsessive–compulsive disorder. Neurosci. Lett , 528 : 27-30.

Halataei B, Khosravi SM, Arbabian S, Sahraei H, Golmanesh L, Zardooz H, Jalili C, Ghoshooni H. 2011. Saffron (Crocus sativus) Aqueous Extract and its Constituent Crocin Reduces Stress‐induced Anorexia in Mice. Phytother Res , 25: 1833-1838.

Hosseinzadeh H, Jahanian Z. 2010. Effect of Crocus sativus L.(saffron) stigma and its constituents, crocin and safranal, on morphine withdrawal syndrome in mice. Phytother Res, 24 : 726-730.

Hosseinzadeh H, Noraei NB. 2009. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res, 23: 768-774.

Kar N. 2011. Cognitive behavioral therapy for the treatment of post-traumatic stress disorder: a review. Neuropsychiatr Dis Treat, 7: 167.

Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, Tsatsakis AM. 2015. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. AJP, 5 :376.

Knapska E, Maren S. 2009. Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. Learn Mem, 16: 486-493.

Kvetnansky R, Sabban EL, Palkovits M. 2009. Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev, 89: 535-606.

Langevin J P, De Salles AAF, Kosoyan HP, Krahl SE. 2010. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res, 44 : 1241-1245.

Maren S, Phan  KL , Liberzon I. 2013. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci, 14 : 417-428.

Marin MF, Camprodon JA, Dougherty DD, Milad MR. 2014. Device-based brain stimulation to augment fear extinction for PTSD treatment and beyond. Depress Anxiety, 31: 269-278.

Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz  D, Hamani C, Schwalb JM , Kennedy SH. 2005. Deep brain stimulation for treatment-resistant depression. Neuron , 45: 651-660.

McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL. 2004. Uncovering the mechanism (s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol, 115: 1239-1248.

Mokhtari-Zaer A, Khazdair MR, Boskabady MH. 2015. Smooth muscle relaxant activity of Crocus sativus (saffron) and its constituents: possible mechanisms. AJP, 5 :365.

Milad MR, Rauch SL, Pitman RK,  Quirk GJ. 2006 . Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol, 73: 61-71.

Noorbala  A, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi A. 2005. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol,  97: 281-284.

Petrov T, Jhamandas JH, Krukoff TL. 1994. Electrical stimulation of the central nucleus of the amygdala induces fos-like immunoreactivity in the hypothalamus of the rat: a quantitative study. Mol Brain Res, 22: 333-340.

Pitsikas N, Boultadakis A, Georgiadou G, Tarantilis P,  Sakellaridis N. 2008. Effects of the active constituents of Crocus sativus L., crocins, in an animal model of anxiety. Phytomedicine, 15: 1135-1139.

Putman P, Hermans EJ, Koppeschaar H, Van Schijndel A,  Van Honk J. 2007. A single administration of cortisol acutely reduces preconscious attention for fear in anxious young men. Psychoneuroendocrinology, 32: 793-802.

Rosa M, Giannicola G, Marceglia S, Fumagalli M, Barbieri S, Priori A. 2012. Neurophysiology of deep brain stimulation. Int Rev Neurobiol , 107: 23-55.

Sahraei H,  Fatahi Z, Eidi A,  Haeri-Rohani A,  Hooshmandi Z, Shekarforoush S, Tavalaei SA. 2012. Inhibiting Post Traumatic Stress Disorder (PTSD) induced by electric shock using ethanol extract of saffron in rats. J. Biol. Res. Thessalon,  18: 320-327.

Schiller D, Monfils MH, Raio CM, Johnson DC, LeDoux JE, Phelps EA. 2010. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature, 463: 49-53.

Stidd DA, Vogelsang K, Krahl SE, Langevin JP, Fellous JM. 2013. Amygdala deep brain stimulation is superior to paroxetine treatment in a rat model of posttraumatic stress disorder. Brain Stimul,  6: 837-844.

Yehuda R. 2009. Status of Glucocorticoid Alterations in Post‐traumatic Stress Disorder. Ann N Y Acad Sci, 1179 : 56-69.

Yehuda R, LeDoux J. 2007. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron, 56: 19-32.

Yu H, Neimat JS. 2008. The treatment of movement disorders by deep brain stimulation. Neurotherapeutics, 5 : 26-36.