Review Article

The effects of Crocus sativus () and its constituents on nervous system: A review

Mohammad Reza Khazdair1, 2, Mohammad Hossein Boskabady1, Mahmoud Hosseini3*, Ramin Rezaee4, Aristidis M. Tsatsakis5

1Neurogenic Inflammation Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Postal Code 9177948564, Iran 2Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran 3Neurocognitive Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Postal Code 9177948564, Iran 4Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran 5Center of Toxicology Science and Research, Division of Morphology, Medical School, University of Crete, Heraklion, Crete, Greece

Article history: Abstract Received: Apr 1, 2015 Saffron or Crocus sativus L. (C. sativus) has been widely used as a Received in revised form: Jun7, 2015 medicinal plant to promote human health, especially in Asia. The Accepted: Jun19, 2015 main components of saffron are , picrocrocin and . Vol. 5, No. 5, Sep-Oct 2015, The median lethal doses (LD50) of C. sativus are 200 mg/ml and 376-391. 20.7 g/kg in vitro and in animal studies, respectively. Saffron has been suggested to be effective in the treatment of a wide range of * Corresponding Author: disorders including coronary artery diseases, hypertension, Tel:+98513800222 stomach disorders, dysmenorrhea and learning and memory Fax:+985138828564 impairments. In addition, different studies have indicated that ‎[email protected] saffron has anti-inflammatory, anti-atherosclerotic, antigenotoxic and cytotoxic activities. Antitussive effects of stigmas and petals Keywords: Crocus sativus of C. sativus and its components, safranal and crocin have also Nervous system been demonstrated. The anticonvulsant and anti-Alzheimer Safranal properties of saffron extract were shown in human and animal Crocin studies. The efficacy of C. sativus in the treatment of mild to Saffron moderate depression was also reported in clinical trial. Administration of C. sativus and its constituents increased glutamate and dopamine levels in the brain in a dose-dependent manner. It also interacts with the opioid system to reduce withdrawal syndrome. Therefore, in the present article, the effects of C. sativus and its constituents on the nervous system and the possible underlying mechanisms are reviewed. Our literature review showed that C. sativus and its components can be

considered as promising agents in the treatment of nervous system disorders. Please cite this paper as: Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, Tsatsakis AM. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed, 2015; 5 (5): 376-391.

AJP, Vol. 5, No. 5, Sep-Oct 2015 376 Crocus sativus (saffron) and nervous system

Introduction total peripheral resistance or both (Fatehi Crocus sativus L (C. sativus), et al., 2003). In rats isolated vas deferens, commonly known as saffron, is a small contractile responses to electrical field perennial plant belonging to the family of stimulation (EFS) were decreased by the Iridaceas. This plant is cultivated in many petals extracts (Fatehi et al., 2003). EFS- countries including Iran, Afghanistan, induced contractions of vas deferens were Turkey and Spain (Abdullaev, 1993). The shown to be mediated by noradrenaline stigmas of C. sativus are known to contain and adenosine triphosphate (ATP) released , α- and as co-transmitters from sympathetic nerves crocin (responsible for saffron yellow (Hoyle and Burnstock, 1991). The color) and picrocrocin, the ethanolic extract made more pronounced aglyconesafranal (responsible for saffron changes in EFS in rats isolated vas aroma) (Fernández and Pandalai, 2004; deferens whereas in guinea pig ileum, the Champalab et al., 2011), the antioxidant aqueous extract of the plant was more carotenoids and and effective (Fatehi et al., 2003). Crocin vitamin B2(Vijaya Bhargava, 2011). analogs isolated from saffron remarkably It has been shown that C. sativus stigma increased the blood flow in the retina and aqueous extract and its constituents, crocin choroid and facilitated function but not safranal enhanced the sexual recovery; therefore, it could be used to activity in male rats (Hosseinzadeh et al., treat ischemic retinopathy and/or age- 2008). Saffron and its constituentscrocin related macular degeneration (Xuan, and safranal are also shown to be potent 1999). One study suggested that saffron radical scavengers (Assimopoulou exerted a significant cardioprotective et al., 2005; Mashmoul et al., 2013; effect by preserving hemodynamics and Farahmand et al., 2013). left ventricular functions (Sachdeva et al., In traditional medicine, C. sativus has 2012). Administration of C. sativus been frequently used as an herbal sedative, extractinpatients who had normal white antispasmodic, aphrodisiac, diaphoretic, blood cells (WBC) count, significantly expectorant, stimulant, stomachic, increased WBC compared to crocin or anticatarrhal, eupeptic, gingival sedative placebo. Moreover, other hematologic and emmenagogue (Nemati et al., 2008). factors were not changed significantly C. sativus was experimentally shown to be during 3 months of the study (Mousavi et effective in relieving symptoms of al., 2015). premenstrual syndrome (PMS). Following A potent stimulatory effect of C. sativus administration of saffron, a significant extract and safranal on β2-adrenoreceptors effect was observed in cycles 3 and 4 in has also been reported (Nemati et al., the Total Premenstrual Daily Symptoms 2008; Boskabady et al., 2010). In addition, and Hamilton Depression Rating Scale blocking effect of safranal on muscarinic which indicates the efficacy of C. sativus receptors (Boskabady et al., 2010) and the in the treatment of PMS (Agha-Hosseini et inhibitory effect of C. sativus on histamine al., 2008). (H1) receptors was reported, which Aqueous (500 mg/kg) and ethanolic proposed a competitive antagonistic effect extracts of C. sativus petals reduced blood for C. sativus on histamine (H1) receptors pressure in a dose-dependent manner in (Boskabady et al., 2010). rats (Fatehi et al., 2003). Administration of An in vitro study showed the inhibitory the aqueous extract of saffron petals (500 activity of saffron and crocin on amyloid mg/kg) reduced blood pressure from beta-peptide fibrillogenesis and its 133.5±3.9 to 117±2.1 mmHg in rats. This protective action against H2O2–induced reduction was postulated to be due to the toxicity in human neuroblastoma cells effect of the extracts on the heart itself, (Papandreou et al., 2006, 2011).

AJP, Vol. 5, No. 5, Sep-Oct 2015 377 Khazdair et al.

Additionally, administration of saffron (60 acid (anionic) dye for biological staining mg/kg body weight, i.p.) to normal and because it has a carboxyl group at each aged mice for one week, significantly end of the polyene chain which is easily improved learning and memory dissolved in aqueous alkali solutions at pH (Papandreou et al., 2011). Also, in vitro ≥ 9. Crocetin is mostly present as trans studies have confirmed the neuroprotective but cis-crocetin and its effects of saffron and its constituents in are also present in saffron as minor amnesic and ischemic rat models components (Melnyk et al., 2010). (Hosseinzadeh and Sadeghnia, 2005; Crocin belongs to a group of natural Ochiai et al., 2007). commercially obtained from Considering clinical and animal the dried stigma of C. sativus. It has a deep experimental studies, the present review red color, forms crystals with a melting explores the important effects of C. sativus point of 186 oC and is easily soluble in and its constituents on nervous system. water. Crocin is responsible for the color of saffron. Structure of crocin was elucidated by Karreeet al (1935). It is the Methods main pigment of saffron (approx. 80% of Information of this review article was pigment content). Pure crocin can be collected by searching for the key-words isolated from saffron extract and is directly "Crocus sativus", "nervous system", crystallized (Karrer et al., 1932). Crocin is "clinical application", "animal studies", not orally absorbed. Crocins are "crocin", "crocetin" and "safranal" in hydrolyzed to crocetin before or during databases namely ISI Web of Knowledge, intestinal absorption, and the absorbed Medline/ Pubmed, Science direct, Scopus, crocetin is partly metabolized to mono and Google Scholar, Embase, Biological diglucuronide conjugates (Asai et al., Abstracts and Chemical Abstracts. 2005). Crocins, accounting for almost 6–16% C. sativus constituents of saffron dry weight (Gregory et al., More than 150 compounds have been 2005), are hydrophilic chemicals. α – identified in saffron stigma including crocin (crocin 1) is a carotenoid which colored carotenoids (e.g. crocetin and comprises the majority of crocins found in crocins as glycosidic derivatives), saffron. It could be so easily dissolved in colorless monoterpene aldehydes, volatile water that is used as color additive agents (e.g. safranal and picrocrocin which (Melnyk et al., 2010). The other color are the bitter components), etc. (Bathaie compounds of saffron are carotenoids and and Mousavi, 2010). The traces of non- glycosidic, alpha-, beta-carotene, glycosylated carotenoids unrelated to lycopene, Zeaxanthingentiobioside, crocetin are β-carotene, lycopene and zea- glycoside, gentio-glycoside, beta-crocetin xanthin (Ríos et al., 1996). Ethanolic di-glycoside and gama-crocetin. extract of saffron has visible absorption Safranal (which is fat soluble) and peaks at 427 and 452 nm. When excited at pigments of the crocetin carotenoid are 435 nm, saffron emits at 543 nm (Horobin bitter, but the most important cause of and Kiernan, 2002). saffron bitterness is picrocrocin Crocetin isolated from saffron is one of (Abdullaev, 1993). Saffron lipophilic the two principal chemicals responsible for carotenoids are lycopene, alpha- and beta- the red color of saffron (Martin et al., carotene and zeaxanthin(Winterhalter and 2002). Crocetin constitutes approximately Straubinger, 2000; Tarantilis and 0.3% of the total weight of the saffron Polissiou, 1997). Kaempferol has also stigma (Escribano et al., 1996, Dris and been found in alcoholic extract of saffron Jain 2004). Crocetin can function as an petals (Gregory et al.,2005). Flavonoids

AJP, Vol. 5, No. 5, Sep-Oct 2015 378 Crocus sativus (saffron) and nervous system especially lycopene, amino acids, proteins, higher than those of carrot and tomato- in starch, resins and other compounds have a concentration and time-dependent also been shown to be present in saffron manner which was accompanied by (Assimopoulou et al.,2005). Saffron also inhibition of Aβ fibrillogenesis. The trans- has trace amounts of thiamine and crocin-4, the digentibiosyl ester of crocetin riboflavin (Alonso et al.,2001). was the main carotenoid constituent which inhibited Aβ fibrillogenesis (Papandreou et Anticonvulsant effects al., 2006). Intracerebroventricular (ICV) In Iranian folk medicine, C. sativus had injection of streptozotocin (STZ) to been used as an anticonvulsant herb rodents has been frequently used as an (Khosravan, 2002). Experimental studies animal model for sporadic AD (Lannert also confirmed saffron anticonvulsant and Hoyer, 1998; Labak et al., 2010; effects in rats and mice (Sunanda et al., Veerendra Kumar and Gupta, 2003). It has 2014; Khosravan, 2002). Saffron at the been previously revealed that treatment by doses of 400 and 800 mg/kg showed a C. sativusextract (30 mg/kg) for 3 weeks significant antiepileptic activity in could significantly improve cognition pentylenetetrazole (PTZ)-induced seizure deficits induced by ICV injection of STZ model in a dose-dependent manner. in rats (Khalili et al., 2010).Crocin (30 However, saffron at the dose of 200 mg/kg mg/kg) has also been shown to have an did not significantly suppress PTZ- antagonizing effect on the STZ-induced induced seizures (Sunanda et al., 2014). cognitive deficits in rats (Khalili and The anticonvulsant activities of aqueous Hamzeh, 2010). and ethanolic extracts of saffron have been Geromichaloset al. (2012) showed that demonstrated in mice using maximal the saffron extract had a moderate (up to electroshock seizure (MES) and PTZ 30 %) inhibitory activity on acetyl- models (Khosravan, 2002). cholinesterase (AChE) and inhibited Safranal (0.15 and 0.35 ml/kg, i.p.), acetylcholine breakdown which is the reduced PTZ-induced seizure duration, main therapeutic approach for AD delayed the onset of tonic convulsions and (Geromichalos et al., 2012). protected mice from death but crocin (200 mg/kg, i.p.) did not show anticonvulsant Clinical studies activity (Hosseinzadeh and Talebzadeh, Administration of saffron 30 mg/day 2005). Intraperitoneal administration of (15 mg twice daily) was found to be as safranal (72.75, 145.5 and 291 mg/kg) effective as donepezil for treatment of decreased the frequency of minimal clonic mild-to-moderate AD in the subjects of 55 seizures (MCS) and generalized tonic years and older (Akhondzadeh et al., clonic seizures (GTCS) (Hosseinzadeh and 2010a ). In addition, the frequency of Sadeghnia, 2007). Safranal also attenuated saffron extract side effects was similar to the acute experimental absence seizures those of donepezil except for vomiting, which was attributed to modifications of which occurred more frequently in the benzodiazepine binding sites of GABAA donepezil group (Akhondzadeh et al., receptor complex (Sadeghnia et al., 2008). 2010a). In another study, 46 patients with mild-to-moderate AD were treated by Anti-Alzheimer effects saffron for 16 weeks. The results showed Basic studies that the cognitive functions in saffron- Alzheimer's disease (AD) is described treated group were significantly better than pathologically as deposition of amyloid β- placebo (Akhondzadeh et al. 2010b). peptide (Aβ) fibrils. The aqueous- ethanolic (50:50, v/v) extract of C. sativus Antidepressant and anti-schizophrenia stigmas has good antioxidant properties - effects

AJP, Vol. 5, No. 5, Sep-Oct 2015 379 Khazdair et al.

Basic studies The effectiveness of C. sativus as a Crocin and ethanolic extracts of saffron treatment for depression in animal model are known to have antidepressant effect in was shown in Table 1. rodents. Using forced swimming test, it was shown that crocin (50–600 mg/kg) Clinical studies reduced immobility time while increased In a randomized and double-blind climbing time (Hosseinzadeh et al., 2003). clinical trial study, saffron In other studies,effectiveness of supplementation statistically improved the antidepressant activity of C. sativus extract mood of subjects compared to the placebo was described (Karimi et al., 2001; Yang group. For six weeks, 30 mg/day of saffron Wang et al., 2010). The petroleum ether was given and subjects were evaluated and dichloromethane fractions were based on the Hamilton Depression Rating suggested to be the active parts of corms Scale (HAM-D) (Akhondzadeh et al., of C. sativus. The petroleum ether fraction 2005). Another similar study by Noorbala of the extract of C. sativus L. corms et al. (2005) revealed that six-week mainly contained n-tridecane, n- administration of saffron extract (30 tetradecane, n-pentadecane, mg/day) was effective in the treatment of diethyltoluamide, n-catane and n- mild to moderate depression. These effects heptadecane, etc. (Yang Wang et al., were similar to the effects of fluoxetine 2010). (Noorbala et al., 2005) and imipramine Kaempferol, a C. sativus petal 100 mg/day (Akhondzadeh et al., 2004). constituent also reduced immobility Therapeutic benefits of petals of C. sativus behaviors in mice (100 and 200 mg/kg) in the treatment of mild to moderate and rats (50 mg/kg) (Hosseinzadeh et al., depression have also been suggested 2007). A decreased time of immobility in (AkhondzadehBasti et al., 2007). The rodents caused by selective serotonin re- efficacy of co-administration of hydro- uptake inhibitors such as fluoxetine may alcoholic extract of C. sativus (40 or 80 explain the antidepressant effects of the mg) and fluoxetine (30 mg/ day) was also plant (Cryan and Lucki, 2000; Lucki, investigated in a double- blind randomized 1997). The antidepressant effect of clinical trial for six weeks. The results aqueous and ethanolic extracts of C. revealed that a dose of C. sativus 80 mg sativus petal and stigma has been shown in plus fluoxetine was more effective than mice (Karimi et al., 2001). Major that of C. sativus 40 mg and fluoxetine to constituents of saffron, safranal and crocin, treat mild to moderate depressive disorders also had antidepressant activity in mice (Moosavi et al., 2014). (Hosseinzadeh et al., 2004).

Table1. The effectiveness of C. sativus as a treatment for depression in animal models.

Constituent Animal Doses Results References

Aqueous and ethanolic Mice (0.2–0.8 g/kg) The aqueous and ethanolic extracts of Hosseinzadeh et al., 2003 extract stigma, reduced immobility time. Aqueous and ethanolic Mice (50–600 mg/kg) Reduced immobility time and increased Hosseinzadeh et al., 2003 extract , Crocin swimming time.

Aqueous and ethanolic Mice (0.15–0.5 mL/kg) Reduced immobility time and increased Hosseinzadeh et al., 2003 extract ,Safranal swimming time. Kaempferol Mice 100 and 200 mg/kg Reduced immobility behaviors Hosseinzadeh et al., 2007

AJP, Vol. 5, No. 5, Sep-Oct 2015 380 Crocus sativus (saffron) and nervous system

Short-term administration of saffron received MPTP or saline over a 30-hour (30 mg/day) capsules for six weeks was period. Animals in the saffron-treated also shown to be as effective as fluoxetine group received Saffron (0.01% w/v) (40 mg/day) in improving depression dissolved in the drinking water for five symptoms in patients who were suffering days and control groups received normal from major depressive disorder (MDD) tap water. After the six days, the brains after undergoing a percutaneous coronary were processed for tyrosine hydroxylase intervention (Shahmansouri et al., 2014). (TH) immunochemistry and TH+ cells Another clinical study demonstrated count was reported using the optical that saffron aqueous extract (15 mg twice fractionator method. In both the SNc and daily) andcrocin (15 mg twice daily) were retina, the MPTP-injected mice had a well tolerated by patients with reduced number of TH+ cells (30-35%) schizophrenia during the study and no compared to saline-injected controls. Pre- serious side effects were observed treatment of MPTP-injected mice by (Mousavi et al., 2015). saffron increased both SNc and retinal The effectiveness of C. sativus as a TH+ cell counts (25-35%) and closed them treatment for depression in human studies to the control levels. It was concluded that was summarized in Table 2. saffron pre-treatment saved many dopaminergic cells in the SNc and retina Anti-Parkinson effects from Parkinsonian (MPTP) insult in mice Saffron and its components (mainly (Purushothuman et al., 2013). crocin, crocetin, and safranal) have been used in animal models with Effects of C. sativus on oxidative neurodegenerative diseases (Ochiai et al., damages and neurotoxicity 2007; Purushothuman et al., 2013). Crocin It has been reported that crocin 10 μM and safranal have inhibitory effect on inhibited the formation of peroxidized fibrillation of apo alpha-lactalbumin (a- lipids in cultured PC12 cells, moderately alpha-LA), under amyloidogenic restored superoxide dismutase (SOD) conditions which crocin was found to be activity and maintained neurons more effective than safranal. Formation of morphology. While the antioxidant effect toxic amyloid structures is related with of crocin was comparable to that of α – various neurodegenerative diseases such as tocopherol, it was even more pronounced Alzheimer’s and Parkinson’s diseases at some concentrations. (Ebrahim-Habibi et al. 2010). Administration of C. sativus stigma Neuroprotective effects of seven-day extract (100 mg/kg, p.o.) for 7 days before administration of crocetin (25, 50 and induction of cerebral by middle 75µg/kg body weight, i.p.) against 6- cerebral artery occlusion (MCAO) hydroxydopamine (6-OHDA, 10 remarkably reduced SOD, catalase and Na, µgintrastriatal)-induced Parkinson's K-ATPase activities and glutamate and disease in rats have been reported. aspartate concentrations induced by Reduction in dopamine utilization by ischemia in rats (Saleem et al. 2006). tissues was suggested as a possible Treatment with saffron extract (5 and 25 mechanism (Ahmad et al., 2005). In mg/ml) and crocin (10 and 50 μM) could another study, the protective effect of decrease the neurotoxic effect of glucose saffron pre-treatment on dopaminergic in PC12 cells. The results showed that cells in the substantia nigra pars compacta glucose (13.5 and 27 mg/ml) reduced (SNc) and retina in a mouse model of PC12 cells viability while cell death was acute MPTP (1-methyl-4-phenyl-1,2,3,6- reduced by saffron and crocin pretreatment tetrahydropyridine)-induced Parkinson's (Mousavi et al., 2010). Another study disease was examined. BALB/c mice showed that administration of saffron

AJP, Vol. 5, No. 5, Sep-Oct 2015 381 Khazdair et al. extract (200 mg/kg) and honey syrup (500 of lipid peroxidation in whole brain and mg/kg) for 45 days reduced the aluminium cerebellum (Linardaki et al., 2013). chloride-induced neurotoxicity in mice It has been suggested that exposure to (Shati et al. 2011). Other studies showed high levels of glucocorticoids or chronic that safranal has some protective effects on stress may lead to oxidative injury in the different markers of oxidative damage in hippocampus, which may impair learning hippocampal tissue from ischemic rats and memory functions (Behl et al., 1997; (Hosseinzadeh and Sadeghnia, 2005) and McIntosh et al., 1998a). Saffron extract in hippocampal tissue following quinolinic and crocin can improve learning and acid (QA) administration (Sadeghnia et al., memory (Abe and Saito, 2000, Pitsikas et 2013). Safranal also reduced extracellular al., 2007). It was demonstrated that saffron concentrations of glutamate and aspartate and crocin can prevent oxidative stress in (excitatory amino acids) in the the hippocampus and avoid deficits in hippocampus of anaesthetized rats spatial learning and memory (Ghadrdoost following administration et al., 2011). It has been reported that (Hosseinzadeh et al. 2008b). crocetin increases the antioxidant potential In addition, crocin increased the activity in brain and helps to fight against 6- of SOD and peroxidase (GPx) OHDA-induced neurotoxicity (Ahmad et and remarkably reduced malondialdehyde al., 2005). (MDA) content in the ischemic cortex in The aqueous extract of saffron (50, 100 rat model of ischemic (Vakili et al., and 200 mg/kg) prevented diazinon (20 2013). Co-administration of saffron extract mg/kg)-induced increase of inflammation, with aluminium reversed aluminium- oxidative stress and neuronal damage induced changes in monoamine oxidase biomarkers (Moallem et al., 2014). (MAO-A, MAO-B) activity and the levels

Table2. The effectiveness of C. sativus as a treatment for depression in human studies.

Number of Treatments Time Results References patients ofTreatme nt (weeks) 30 Stigma of C. sativus30 6 The effect of stigma of C. sativussimilar to Akhondzadeh et al.,2004 mg/day imipramine in the treatment of mild to moderate depression 40 Stigma of C. sativus30 6 The outcome on the Hamilton depression Akhondzadeh et al.,2005 mg/day rating scale Stigma of C. sativuscould produce a significantly better than the placebo 40 Stigma of C. sativus30 6 The effect of stigma of C. sativussimilar to Noorbala et al.,2005 mg/day fluoxetine in the treatment of mild to moderate depression

40 Petal of C. sativus30 mg/day 6 The outcome on the Hamilton depression Moshiri et al.,2006 rating scale Petal of C. sativuscould produce a significantly better than the placebo

40 Petal of C. sativus15 mg bid 8 Petal of C. sativuswas found to be effective AkhondzadehBasti et al., (morning and evening) similar to fluoxetine in 2007 The treatment of mild to moderate depression 60 C. sativus40 and 80 mg/day+ 6 Was effective to treatment of mild to Moosavi et al., 2014 fluoxetine (30 mg) moderate depressive disorders 40 Saffron(30 mg/day 6 Was effective as fluoxetine (40 mg/day) in Shahmansouri et al., 2014 improving depressive symptoms of patients who are suffering from major depressive disorder (MDD)

AJP, Vol. 5, No. 5, Sep-Oct 2015 382 Crocus sativus (saffron) and nervous system

Effects of C. sativus on neuronal injury serum/glucose deprivation (Ochiai et al., and apoptosis 2004a). Crocin (30, 60 and 120 mg/kg) showed Crocin and tricrocin remarkably protective effect against suppressed membrane lipid peroxidation, ischemia/reperfusion injury and cerebral caspase-3 activation and cell death in edema in a rat model of stroke and serum-deprived and hypoxic PC12 cells decreased infarct volume. Administration which were more marked than those of of crocin (60 mg/kg), one hour before, or tricrocin. Crocetin has been suggested to one hour after the induction of ischemia, have some linked glucose esters (Ochiai et reduced brain edema (Vakili et al., 2013). al., 2007). The results of this study The neuroprotective effects of crocetin in suggested that dicrocin and picrocrocin the brain injury in animal studies have had no effect on cell survival (Ochiai et been suggested to be related to its ability al., 2007). to inhibit apoptosis at early stages of the injury and its ability to promote Effects of C. sativus on angiogenesis at the subacute stage as neuroinflammation directed by higher expression levels of Crocin inhibited syncytin-1 and nitric vascular endothelial growth factor oxide (NO)-induced astrocyte and receptor-2 (VEGFR-2) and serum response oligodendrocyte cytotoxicity (Christensen, factor (SRF) (Bie et al., 2011). 2005) and reduced neuropathology in A recent study showed that crocin experimental autoimmune (50 mg/kg) prevented retinalganglion cells encephalomyelitis (EAE) with (RGCs) apoptosis after retinal significantly less neurological ischemia/reperfusion injury via impairments. Syncytin-1 has been phosphatidylinositol 3-kinase/AKT contributed to oligodendrocyte death and (PI3K/AKT) signaling pathway. In neuroinflammation (Christensen, 2005; addition, crocin increased Bcl-2/BAX ratio Antony et al., 2004). Syncytin-1 is highly (Qi et al., 2013). Crocin (10 µM)could expressed in astrocytes, microglia and in suppress tumor necrosis factor alpha the glial cells of multiple sclerosis lesions (TNF-α)-induced expression of (Barnett and Prineas, 2004). proapoptotic mRNA which releases Endoplasmic reticulum (ER) stress has cytochrome c from mitochondria and it been shown to be closely related to was suggested that crocin inhibits neuronal inflammatory pathways (Mori, 2009). It cell death induced by both internal and was shown that EAE increases the external apoptotic stimuli (Soeda et al., transcript levels of the ER stress genes 2001). Moreover, crocetin can inhibit XBP-1/s (Marciniak et al., 2004). H2O2-induced RGC-5 cell death and Administration of crocin on day 7 post- inhibit caspase-3 and caspase-9 activity EAE induction, suppressed ER stress and (Yamauchi et al., 2011). inflammatory gene expression in the spinal In serum/glucose-deprived cells, lipid cord and also reduced the expression of peroxidation may increase which can be ER stress genes XBP-1/s (Deslauriers et inhibited by crocin. Crocin can suppress al., 2011). the activation of caspase-8 was and its antioxidant properties are more C. sativus and the brain prounounced than α-tocopherol at the neurotransmitters same concentration (Ochiai et al., 2004). Ettehadi et al. (2013) showed that the In addition, crocin suppressed the aqueous extract of saffron (50, 100, 150 activation of caspase-8 caused by and 250 mg/kg, i.p.) increased brain

AJP, Vol. 5, No. 5, Sep-Oct 2015 383 Khazdair et al. dopamine concentration in a dose- induced by naloxone in mice dependent manner. Moreover, the extract (Hosseinzadeh and Jahanian, 2010). Also, had no effect on brain serotonin or crocin (200 and 600 mg/Kg) could reduce norepinephrine concentration. In addition, withdrawal sign without reducing the results showed that the aqueous extract locomotor activities (Amin and of saffron especially at the dose of 250 Hosseinzadeh, 2012; Hosseinzadeh and mg/kg triggered and increased the Jahanian, 2010). production of important neurotransmitters Intraperitoneal administration of including dopamine and glutamate in rat ethanolic extract of saffron (10, 50 and brain (Ettehadi et al., 2013). 100 mg/Kg) and safranal (1, 5 and 10 The effects of saffron on conditioning mg/Kg) reduced theacquisition and place preference (CPP) induced by expression of morphine CPP (Ghoshooniet morphine has been reported to be similar al., 2011). Administration of crocin (400 to the effect of N-methyl-D-aspartate and 600 mg/kg,i.p.) 30 min before (NMDA) receptor antagonists morphine administration decreased the (Hosseinzadeh et al., 2012 Lechtenberg et acquisition and reinstatement of morphine- al., 2008). Furthermore, the analgesic induced CPP in mice (Imenshahidi et al., effect of saffron can be reduced by NMDA 2011). It has also been reported that 5 min receptor antagonists (Nasri et al., 2011). after morphine (10 mg/kg) administration, Therefore an interaction with injection of ethanolic extract of C. sativus system for saffron of its stigma (5 and 10 µg/rat) into the nucleus components might be postulated. accumbens shell part of rats, led to The NMDA receptors have also been decrease in the time spent in drug paired well known to be involved in post-training side. In addition, injection of extract to the memory processing by the amygdala and animals that received morphine (10 hippocampus (Izquierdo et al., 1992). The mg/kg), decreased the expression of role of these receptors in morphine state- morphine (CPP) (Mojabi et al., 2008). dependent learning has also been Injection of aqueous extract of saffron suggested (Zarrindast et al., 2006; Cestari stigma (50, 100, 150 and 250mg/Kg,i.p.) and Castellano, 1997). Involvement of showed an increased release of dopamine NMDA receptors in the effects of C. in rat brains. Also, this extract (only at 250 sativus or its constituents on memory has mg/Kg) significantly increased the release been shown (Lechtenberg et al., 2008; Abe of glutamate (Ettehadi et al., 2013). et al., 1999). The beneficial effects of Administration of saffron extract (150 saffron on memory have also been and 450 mg/kg) before retention trials also suggested to be mediated by the increased the time latency. So, saffron cholinergic system (Pitsikas and extract reduced morphine-induced memory Sakellaridis, 2006; Ghadami and impairment (Naghibi et al., 2012). Pourmotabbed, 2009). Protective effect of saffron extract against morphine-induced inhibition of spatial C. sativus and opioids system learning and memory in rat has also been Saffron aqueous (80–320 mg/kg) and suggested (Haghighizad et al., 2008). ethanolic (400–800 mg/kg) extracts The effects of C. sativus on opioid reduced morphine withdrawal signs receptors were showed in Table 3.

AJP, Vol. 5, No. 5, Sep-Oct 2015 384 Crocus sativus (saffron) and nervous system

Table 3. The effects of C. sativus on opioid system

C. Sativus or its Dose Results References constituents Saffron 150 and 450 mg/kg Improved learning and memory Naghibi et al., 2012 impairment induced by morphine Saffron Aqueous (80, 160, 320 mg/kg) and Reduced naloxone precipitated jumping Ghoshooni et al., 2011; ethanolic (400 and 800 mg/kg) shams et al., 2009 extract

Crocin 200 and 600 mg/kg Reduced withdrawal sign without reducing Amin and hosseinzadeh locomotor activity 2012 C. sativusstigma extract (5 and 10 µg/rat) Decrease in the time spent in drug paired Ghoshooni et al., 2011 side Crocin 400 and 600 mg/kg Decreased the acquisition and reinstatement of morphine-induced cpp Saffron 10, 50 and 100 mg/kg Reduced the acquisition and expression of morphine cpp Safranal 1, 5 and 10 mg/kg Reduced the acquisition and expression of morphine cpp Saffron 50, 100, 150 and 250mg/kg Increased the release of dopamine in rat Ettehadi et al., 2013 brains and increased the release of glutamate only in dose 250

Conclusion References Anti-oxidant and anti-inflammatory Abdullaev F. 1993. Biological effects of effects of the extracts of C. sativus and its saffron. BioFactors (Oxford, England), constituents (crocetin, crocins, safranal) 4:83-86 implies saffron therapeutic potential for Abe K,Saito H. 2000. Effects of saffron various nervous system disorders. Based extract and its constituent crocin on on the literature, beneficial effects of the learning behaviour and long-term plant and its components on potentiation.Phytother Res, 14: 149–152. neurodegenerative disorders such as Abe K, Sugiura M, Yamaguchi S, Shoyama Y, Alzheimer and Parkinson's disease are Saito H. 1999.Saffron extract prevents mainly due to their interactions with acetaldehyde-induced inhibition of long- cholinergic, dopaminergic and term potentiation in the rat dentate gyrus in glutamatergic systems. It is assumed that vivo. Brain Res, 851: 287–289. saffron anticonvulsant and analgesic Agha‐Hosseini M, Kashani L, Aleyaseen A, properties and its effects on morphine Ghoreishi A, Rahmanpour H, Zarrinara A, Akhondzadeh S. 2008. Crocus sativus withdrawal and rewarding properties of L.(saffron) in the treatment of premenstrual morphine might be due to an interaction syndrome: a double‐blind, randomised and between saffron, GABA and opioid placebo‐controlled trial. BJOG: Int J system. Gynaecol Obstet, 115:515-519 According to human and animal Ahmad AS, Ansari MA, Ahmad M, Saleem S, studies, saffron and its constituents have Yousuf S, Hoda MN, Islam F. 2005. been shown to be effective in the treatment by crocetin in a hemi- of mild to moderate depression which may parkinsonian rat model. Pharmacol be because of an interaction with the Biochem Behav, 81:805-813. serotonin and noradrenaline system. Akhondzadeh Basti A, Moshiri E, Noorbala However, to have a detailed perspective of AA, Jamshidi AH, Abbasi SH, saffron effects on nervous system, more Akhondzadeh S. 2007. Comparison of petal mechanistic investigations are highly of Crocus sativus L. and fluoxetine in the advised. treatment of depressed outpatients: A pilot double-blind randomized trial. Prog Conflict of interest Neuropsychopharmacol Biol There is no conflict of interest. Psychiatry, 31:439-442.

AJP, Vol. 5, No. 5, Sep-Oct 2015 385 Khazdair et al.

Akhondzadeh S, Fallah-Pour H, Afkham K, crocetin and its glucuronide conjugates in Jamshidi A-H, Khalighi-Cigaroudi F. 2004. mice. J Agric Food Chem, 53:7302-7306 Comparison of Crocus sativus L. and Assimopoulou A, Sinakos Z, Papageorgiou V. imipramine in the treatment of mild to 2005. Radical scavenging activity of moderate depression: a pilot double-blind Crocus sativus L. extract and its bioactive randomized trial. BMC Complement Altern constituents. Phytother Res, 19:997-1000 Med,4:12. Bathaie SZ, Mousavi SZ. 2010. New Akhondzadeh S, Sabet MS, Harirchian M, applications and mechanisms of action of Togha M, Cheraghmakani H, Razeghi S, saffron and its important ingredients. Crit Hejazi SS, Yousefi M, Alimardani R, Rev Food Sci Nutr, 50:761-786. Jamshidi A. 2010a. Saffron in the treatment Barnett MH, Prineas JW. 2004. Relapsing and of patients with mild to moderate remitting multiple sclerosis: pathology of Alzheimer’s disease: a 16‐week, the newly forming lesion. Ann Neurol, 55: randomized and placebo‐controlled trial. J 458–468 Clin Pharm Therapeut, 35:581-588. Behl C, Lezoualc'h F, Trapp T, Widmann M, Akhondzadeh S, Sabet MS, Harirchian MH, Skutella T, Holsboer F. 1997. Togha M, Cheraghmakani H, Razeghi S, Glucocorticoids enhance oxidative stress- Hejazi SS, Yousefi MH, Alimardani R, induced cell death in hippocampal neurons Jamshidi A. 2010b. A 22-week, in vitro. Endocrinology, 138: 101–106. multicenter, randomized, double-blind Bhargava V. 2011. Medicinal uses and controlled trial of Crocus sativus in the pharmacological properties of Crocus treatment of mild-to-moderate Alzheimer’s sativus Linn (Saffron). Int J Pharmacy disease. Psychopharmacology, 207:637- Pharmaceutical Science, 3:22-26 643. Bie XD, Chen YQ, Zheng XS, Dai HB .2011. Akhondzadeh S, Tahmacebi‐Pour N, Noorbala The role of crocetin in protection following AA, Amini H, Fallah‐Pour H, Jamshidi cerebral contusion and in the enhancement AH, Khani M. 2005. Crocus sativus L. in of angiogenesis in rats. Fitoterapia, 82:997– the treatment of mild to moderate 1002. depression: a double‐blind, randomized and Bieschke J, Zhang Q, Powers ET, Lerner RA, placebo‐controlled trial. Phytother Res, Kelly JW. 2005. Oxidative metabolites 19:148-151. accelerate Alzheimer's amyloidogenesis by Alonso Gl, Salinas MR, Garijo J, Sánchez‐ a two-step mechanism, eliminating the Fernández MA. 2001. Composition of requirement for nucleation. Biochemistry, crocins and picrocrocin from Spanish 44: 4977-4983. saffron (Crocus sativus L.). JFood Quality, Boskabady MH, Rahbardar MG, Nemati H, 24:219-233. Esmaeilzadeh M. 2010. Inhibitory effect of Amin B, Hosseinzadeh H. 2012. Evaluation of Crocus sativus (saffron) on histamine (H1) aqueous and ethanolic extracts of saffron, receptors of guinea pig tracheal chains. Die Crocus sativus L., and its constituents, Pharmazie Int J Pharm Sci, 65:300-305. safranal and crocin in allodynia and Cestari V and Castellano C. 1997. “MK-801 hyperalgesia induced by chronic potentiates morphine-induced impairment constriction injury model of neuropathic of memory consolidation in pain in rats. Fitoterapia, 83:888-895. mice:involvement of dopaminergic Antony JM, van Marle G, Opii W, Butterfield mechanisms,” Psychopharma-cology, 133, DA, Mallet F,Yong VW, Wallace JL, :1–6. Deacon RM, Warren K, Power C. 2004. Christensen, T.2005. Association of human Human endogenous retrovirus endogenous retroviruses with multiple glycoprotein-mediated induction of redox sclerosis and possible interactions with reactants causes oligodendrocyte death and herpes viruses. Rev Med Virol, 15: 179– demyelination. Nat Neurosci. 7: 1088– 211. 1095. Cryan JF, Lucki I. 2000. Antidepressant-like Asai A, Nakano T, Takahashi M, Nagao A. behavioral effects mediated by 5- 2005. Orally administered crocetin and hydroxytryptamine2C receptors. J crocins are absorbed into as Pharmacol Exp Therapeut, 295:1120-1126.

AJP, Vol. 5, No. 5, Sep-Oct 2015 386 Crocus sativus (saffron) and nervous system

Deslauriers AM, Afkhami-Goli A, Paul AM, induced spatial learning and memory Bhat RK, Acharjee S, Ellestad KK, deficits in rats. Physiol Pharmacol, 12:287– Noorbakhsh F, Michalak M, Power C. 295. 2011. Neuroinflammation and endoplasmic Ghadrdoost B, Vafaei AA, Rashidy-Pour A, reticulum stress are coregulated by crocin Hajisoltani R, Bandegi AR, Motamedi F, to prevent demyelination and Haghighi S, Sameni HR, Pahlvan S. 2011. neurodegeneration. J Immunol, 87:4788- Protective effects of saffron extract and its 99. active constituent crocin against oxidative Dris R, Jain SM. 2004. Production practices stress and spatial learning and memory and quality assessment of food crops.2004. deficits induced by chronic stress in rats. Volume 1 Preharvest Practice. Dris, Eur J Pharmacol, 667:222-229. Ramdane, Jain, S. Mohan (Eds.) Springer. Ghoshooni H, Daryaafzoon M, Sadeghi- Ebrahim-Habibi MB, Amininasab M, Gharjehdagi S, Zardooz H, Sahraei H, Ebrahim-Habibi A, Sabbaghian M, Nemat- Tehrani SP, et al. 2011. Saffron (Crocus Gorgani M. 2010. Fibrillation of alpha- sativus) ethanolic extract and its lactalbumin: effect of crocin and safranal, constituent, safranal, inhibits morphine- two natural small molecules from Crocus induced place preference in mice. Pak J sativus. Biopolymers, 93:854–865. Biol Sci, 14:939-944. Ettehadi Hosseinali, Seyedeh Nargesolsadat Gregory MJ, Menary RC, Davies NW. 2005. Mojabi, Mina Ranjbaran, Jamal Shams, Effect of drying temperature and air flow Hedayat Sahraei, Mahdi Hedayati, and on the production and retention of Farzad A. 2013. Aqueous Extract of secondary metabolites in saffron. JAgric Saffron (Crocus sativus) Increases Brain Food Chem, 53:5969-5975. Dopamine and Glutamate Concentrations Haghighizad H, Pourmotabbed A, Sahraei H. in Rats. J Behav Brain Sci, 3:315-319. 2008. Protective effect of Saffron extract on Escribano J, Alonso G-L, Coca-Prados M, morphine-induced inhibition of spatial Fernández J-A. 1996. Crocin, safranal and learning and memory in rat. Physiol picrocrocin from saffron (Crocus sativus Pharmacol, 12: 170–179. L.) inhibit the growth of human Horobin RW, Kiernan JA, Commission BS. cells in vitro. Cancer letters, 100:23-30. 2002. Conn's biological stains: a handbook Farahmand SK, Samini F, Samini M, of dyes, stains and fluorochromes for use in Samarghandian S. 2013. Safranal biology and medicine. Biological Stain ameliorates antioxidant enzymes and Commission. suppresses lipid peroxidation and nitric Hosseinzadeh H, Jahanian Z. 2010. Effect of oxide formation in aged male rat liver. Crocus sativus L. (saffron) Stigma and its Biogerontology, 14: 63-71. Constituents, Crocin and Safranal, on Fatehi M, Rashidabady T, Fatehi-Hassanabad Morphine Withdrawal Syndrome in Z. 2003. Effects of Crocus sativus petals’ Mice. Phytother Res, 24: 726-730. extract on rat blood pressure and on Hosseinzadeh H, Karimi G, Niapoor M. 2004. responses induced by electrical field Antidepressant effect of Crocus sativus stimulation in the rat isolated vas deferens L. stigma extracts and their constituents, and guinea-pig ileum. J crocin and safranal, in mice. Acta Hort, ethnopharmacology, 84:199-203 650: 435-45. Fernández J-A, Pandalai S. 2004. Biology, Hosseinzadeh H, Motamedshariaty V, biotechnology and biomedicine of saffron. Hadizadeh F. 2007. Antidepressant effect Recent Res Devel Plant Sci, 2:127-159 of kaempferol, a constituent of saffron Geromichalos GD, Lamari FN, Papandreou (Crocus sativus) petal, in mice and rats. MA, Trafalis DT, Margarity M, Pharmacologyonline, 2:367-370. Papageorgiou A, Sinakos Z. 2012. Saffron Hosseinzadeh H, Sadeghnia, HR. 2005. as a source of novel acetylcholinesterase Safranal, a constituent of Crocus sativus inhibitors: molecular docking and in vitro (saffron), attenuated cerebral ischemia enzymatic studies. J Agric Food Chem, induced oxidative damage in rat 60:6131-6138. hippocampus. J PharmPharm Sci, 8, 394– Ghadami MR and Pourmotabbed A. 2009. 399. The effect of crocin on scopolamine

AJP, Vol. 5, No. 5, Sep-Oct 2015 387 Khazdair et al.

Hosseinzadeh H, Sadeghnia HR, Rahimi A Model of Alzheimer Disease in Rats. Iran J .2008b. Effect of safranal on extracellular Pathol, 5:27-33. hippocampal levels of glutamate and Khavandgar S, Homayoun H, Zarrindast MR. aspartate during kainic acid treatment in 2003. The effect of L-NAME and L- anesthetized rats. Planta Med, 74:1441– arginine on impairment of memory 1445. formation and state-dependent learning Hosseinzadeh H, Talebzadeh F. 2005. induced by morphine in mice. Anticonvulsant evaluation of safranal and Psychopharmacology, 167: 291–296. crocin from Crocus sativus in mice. Khosravan V. 2002. Anticonvulsant effects of Fitoterapia, 76:722-724. aqueous and ethanolic extracts of Crocus Hosseinzadeh H, ziaee T, sadeghi A. 2008. sativus L. stigmas in mice. Arc Iran Medi, The effect of saffron, crocus sativus stigma, 5:44. extract and its constituents, safranal and Labak M, Foniok T, Kirk D, Rushforth D, crocin on sexual behaviors in normal male Tomanek B, Jasiński A, Grieb P. 2010. rats. Phytomedicine, 15:491–495. Metabolic changes in rat brain following Hosseinzadeh H, Sadeghnia HR. 2007. intracerebroventricular injections of Protective effect of safranal on streptozotocin: a model of sporadic pentylenetetrazol-induced seizures in the Alzheimer’s disease. Brain Edema XIV, rat: involvement of GABAergic and Springer. opioids systems. Phytomedicine, 14, 256- Lannert H, Hoyer S. 1998. 62. Intracerebroventricular administration of Hoyle CH, Burnstock G. 1991. ATP receptors streptozotocin causes long-term and their physiological roles. Adenosine in diminutions in learning and memory the Nervous System:43-76. abilities and in cerebral energy metabolism Imenshahidi M, Zafari H, Hosseinzadeh H. in adult rats. Behav Neurosci, 112:1199. 2011. Effects of crocin on the acquisition Lechtenberg MD, Schepmann M, Niehues N, and reinstatement of morphine-induced Hellenbrand B, ¨unsch W, Hensel A. 2008. conditioned place preference in mice. Quality and functionality of saffron: quality Pharmacologyonline, 1: 1007-1013. control, species assortment and affinity of Izquierdo C. Da Cunha, Rosat R, Jerusalinsky extract and isolated sa ff ron compounds to D, Ferreira MBC and Medina JH.1992. NMDA and σ 1(Sigma-1) receptors, Planta Neurotransmitter receptors involved in Medica, 74: 764–772. post-training memory processing by the Lechtenberg M, Schepmann D, Niehues M, amygdala, medial septum, and Hellenbrand N, unsch WB, Hensel hippocampus of the rat. Behav Neur Biol, A.2008.Quality and functionality of 58: 16–26. saffron: quality control, species assortment Karimi GR, Hosseinzadeh H, KHALEGH PP. and affinity of extract and isolated saffron 2001. Study of antidepressant effect of compounds to NMDA and σ 1(Sigma-1) aqueous and ethanolic extract of Crocus receptors. Plant Med, 74: 764–772, sativus in mice. Iran J Basic Med Sci, 4: Linardaki ZI, Orkoula MG, Kokkosis AG, 11-15. Lamari FN, Margarity M .2013. Karrer P, Benz F, Morf R, Raudnitz H, Stoll Investigation of the neuroprotective action M, Takahashi T. 1932. Pflanzenfarbstoffe of saffron (Crocus sativus L.) in XLVI. Konstitution des Crocetins und aluminumexposed adult mice through Bixins. Synthese des Perhydro‐norbixins. behavioral and neurobiochemical Helvetica Chimica Acta, 15:1399-1419. assessment. Food Chem Toxicol, 52:163– Khalili M, Hamzeh F. 2010. Effects of active 170. constituents of Crocus sativus L., crocin on Lucki I. 1997. The forced swimming test as a streptozocin-induced model of sporadic model for core and component behavioral Alzheimer's disease in male rats. Iran effects of antidepressant drugs. Behav Biomed J, 14:59. pharmacol, 8:523-532. Khalili M, Kiasalari Z, Rahmati B, Narenjkar Marciniak SJ, Yun CY, Oyadomari S, Novoa J. 2010. Behavioral and Histological I, Zhang Y, Jungreis R, Nagata K, Harding Analysis of Crocus Sativus Effect in HP, Ron D. 2004. CHOP induces death by Intracerebroventricular Streptozotocin promoting protein synthesis and oxidation

AJP, Vol. 5, No. 5, Sep-Oct 2015 388 Crocus sativus (saffron) and nervous system

in the stressed endoplasmic reticulum. sativus) and its constituents crocin and Genes Dev. 18: 3066. safranal. Kowsar Med J, 15: 189–195. Mashmoul M, Azlan A, Khaza'ai H, Yusof Nemati H BM, Ahmadzadef Vostakolaei H. Bnm, Noor Sm. 2013. Saffron: A natural 2008. Stimulatory effect of crocus sativus potent antioxidant as a promising anti- (saffron) on beta2-adrenoceptors of guinea obesity drug. Antioxidants, 2: 293-308. pig tracheal chains. Phytomedicine Martin G, Goh E, Neff A. 2002. Evaluation of 15:1038-1045. the developmental toxicity of crocetin on Nilakshi N, Gadiya RV, Abhyankar M, Xenopus. Food chem toxicol, 40:959-964 Champalal KD. 2011. Detailed profile of Melnyk JP, Wang S, Marcone MF. 2010. Crocus sativus. Int J Pharma Bio Sciences, Chemical and biological properties of the 2: 530-540. world's most expensive spice: Saffron. Noorbala A, Akhondzadeh S, Tahmacebi-Pour Food Res Int, 43:1981-1989. N, Jamshidi A. 2005. Hydro-alcoholic Moallem SA, Hariri AT, Mahmoudi M, extract of Crocus sativus L. versus Hosseinzadeh H. 2014. Effect of aqueous fluoxetine in the treatment of mild to extract of Crocus sativus L. (saffron) moderate depression: a double-blind, stigma against subacute effect of diazinon randomized pilot trial. J Ethnopharmacol, on specific biomarkers in rats. Toxicol Ind 97:281-284. Health, 30:141-6. Ochiai T, Ohno S, Soeda S, Tanaka H, Moshiri E, Akhondzadeh BastiA, Noorbala Shoyama Y, Shimeno H .2004a. Crocin AA, Jamshidi AH, Abbasi SH, prevents the death of rat pheochromyctoma Akhondzadeh S. 2006. Crocus sativus (PC-12) cells by its antioxidant effects L.(petal) in the treatment of mild-to- stronger than those of α -tocopherol. moderate depression: A double-blind, Neurosci Lett, 362:61–64. randomized and placebo-controlled trial. Ochiai T, Shimeno H, Mishima K, Iwasaki K, Phytomedicine, 13: 607-611. Fujiwara M, Tanaka H, Shoyama Y, Toda Moosavi SM, Ahmadi M, Amini M, A, Eyanagi R, Soeda S. 2007. Protective Vazirzadeh B, Sari I. 2014. The Effects of effects of carotenoids from saffron on 40 and 80 mg Hydro-alcoholic Extract of neuronal injury in vitro and in vivo. Crocus Sativus in the Treatment of Mild to Biochim Biophys Acta, 1770: 578-584. Moderate Depression. J Mazandaran Univ Ochiai T, Soeda S, Ohno S, Tanaka H, Med Sci (JMUMS) 24. Shoyama Y, Shimeno H. 2004. Crocin Mousavi B BS, Fadai F, Ashtari Z, Ali beige prevents the death of PC-12 cells through N, Farhang S, Hashempour S, Shahhamzei sphingomyelinase-ceramide signaling by N, Heidarzadeh H. 2015. Safety evaluation increasing glutathione of saffron stigma (Crocus sativus L.) synthesis.Neurochem Int. 44:321-330. aqueous extract and crocin in patients with Papandreou MA, Polissiou MG, schizophrenia. Avicenna J Phytomed, Efthimiopoulos S, Cordopatis P, Margarity Epub. M, Lamari FN. 2006. Inhibitory activity on Mousavi SH, Tayarani NZ, Parsaee H.2010. amyloid-beta aggregation and antioxidant Protective effect of saffron extract and properties of Crocus sativus stigmas extract crocin on reactive oxygen species-mediated and its crocin constituents. J Agric Food high glucose-induced toxicity in PC12 Chem, 54:8762-8768. cells. Cell Mol Neurobiol, 30:185–191. Papandreou MA, Tsachaki M, Efthimiopoulos Naghibi SM, Mahmoud Hosseini, Fatemeh S, Cordopatis P, Lamari FN, Margarity M. Khani, Motahare Rahimi, Farzaneh 2011. Memory enhancing effects of saffron Vafaee, Hassan Rakhshandeh, and Azita in aged mice are correlated with Aghaie. 2012. Effect of Aqueous Extract antioxidant protection. Behav Brain Res, ofCrocus sativus L. on Morphine-Induced 219:197-204. Memory Impairment. Adv Pharmacol Sci, Pitsikas N, Zisopoulou S, Tarantilis PA, Article ID 494367, 7 pages. Kanakis CD, Polissiou MG, Sakellaridis N. Nasri S, Sahraei H, Zardooz H. 2011. 2007. Sakellaridis.Effects of the active Inhibition of pain and inflamation induced constituents of Crocus sativusL., crocins on by formalin in male mice by recognition and spatial rats' memory. ethanolicextract of sa ff ron (Crocus Behav Brain Res, 83:141-146.

AJP, Vol. 5, No. 5, Sep-Oct 2015 389 Khazdair et al.

Pitsikas N and Sakellaridis N. 2006. Crocus Shati AA, Elsaid FG, Hafez EE .2011. sativus L. extracts antagonize memory Biochemical and molecular aspects of impairments in di ff erent behavioural tasks aluminium chloride-induced neurotoxicity in the rat. Behav Brain Res, 173: 112–115. in mice and the protective role of Crocus Purushothuman S, Nandasena C, Peoples CL, sativus L. extraction and honey syrup. El Massri N, Johnstone DM, Mitrofanis J, Neuroscience, 175:66–74. Stone J. 2013. Saffron pre-treatment offers Soeda S, Ochiai T, Paopong L, Tanaka H, neuroprotection to Nigral and retinal Shoyama Y, Shimeno H. 2001. Crocin dopaminergic cells of MPTP-Treated suppresses tumor necrosis factor-alpha- mice.J Parkinsons Dis, 3:77-83. induced cell death of neuronally Rios J, Recio M, Giner R, Manez S. 1996. An differentiated PC-12 cells. Life Sci, update review of saffron and its active 69:2887-2898. constituents. Phytother Res, 10:189-193. Sugiura M, Shoyama Y, Saito H, Abe K. Qi Y, Chen L, Zhang L, Liu WB, Chen XY, 1994. Crocin (crocetin di-gentiobiose ester) Yang XG. 2013. Crocin prevents retinal prevents the inhibitory effect of ethanol on ischaemia/reperfusion injury-induced long-term potentiation in the dentate gyrus apoptosis in retinal ganglion cells through in vivo. J Pharmacol Exper Therap, the PI3K/AKT signalling pathway. Exp 271:703–707. Eye Res, 107:44-51. Sunanda BPV, RammohanB, Amitabh kumar, Sachdeva J, Tanwar V, Golechha M, Siddiqui Kudagi BL. 2014. The effective study of KM, Nag TC, Ray R, Kumari S, Arya DS. aqueous extract of crocus sativus linn. In 2012. Crocus sativus L.(saffron) attenuates chemical induced convulsants in rats. isoproterenol-induced myocardial injury World J Pharm Pharm Sci, 3,1175-1182. via preserving cardiac functions and Srivastava R, Ahmed H, Dixit R. 2010. Crocus strengthening antioxidant defense system. sativus L.: a comprehensive review. Exper Toxicol Pathol, 64:557-564. Pharmacogn Rev, 4:200. Sadeghnia HR, Kamkar M, Assadpour E, Tarantilis PA, Polissiou MG. 1997. Isolation Boroushaki MT, Ghorbani A .2013. and identification of the aroma components Protective effect of safranal, a constituent from saffron (Crocus sativus). J Agricul of Crocus sativus , on - Food Chem, 45:459-462. induced oxidative damage in rat Vakili A, Einali MR, Bandegi AR .2013. hippocampus. Iran J Basic Med Sci, Protective Effect of crocin against cerebral 16:73–82. ischemia in a dose- dependent manner in a Sadeghnia H, Cortez M, Liu D, Hosseinzadeh rat model of ischemic stroke. J Stroke H, Snead 3rd OC. 2008. Antiabsence Cerebrovasc Dis S1052–3057(12)00345-X effects of safranal in acute experimental (in press). seizure models: EEG and autoradiography. Veerendra Kumar M, Gupta Y. 2003. Effect of J Pharm Pharm Sci, 11:1-14. Centella asiatica on cognition and oxidative Saleem S, Ahmad M, Ahmad AS, Yousuf S, stress in an intracerebroventricular Ansari MA, Khan MB, Ishrat T, Islam F streptozotocin model of Alzheimer's .2006. Effect of Saffron ( Crocus sativus ) disease in rats. Clin Experiment Pharmacol on neurobehavioral and neurochemical Physiol, 30: 336-342. changes in cerebral ischemia in rats. J Med Wang Y, Han T, Zhu Y, Zheng C-J, Ming Q- Food, 9:246–253. L, Rahman K, Qin L-P. 2010. Shahmansouri N, Farokhnia M, Abbasi S-H, Antidepressant properties of bioactive Kassaian SE, Noorbala Tafti A-A, Gougol fractions from the extract of Crocus sativus A, Yekehtaz H, Forghani S, Mahmoodian L. J Nat Med,64:24-30. M, Saroukhani S. 2014. A randomized, Winterhalter P, Straubinger M. 2000. double-blind, clinical trial comparing the Saffron—renewed interest in an ancient efficacy and safety of Crocus sativus L. spice. Food Rev Int, 16:39-59. with fluoxetine for improving mild to Xuan B, Zhou Y-H, Li N, Min Z-D, Chiou moderate depression in post percutaneous GC. 1999. Effects of crocin analogs on coronary intervention patients. J Affect ocular blood flow and retinal function.J Disord,155:216-222. Ocular Pharmacol Therap, 15:143-152.

AJP, Vol. 5, No. 5, Sep-Oct 2015 390 Crocus sativus (saffron) and nervous system

Yamauchi M, Tsuruma K, Imai S, Nakanishi Zhang YY. Shoyama, M. Sugiura, Saito H. T, Umigai N, Shimazawa M, Hara H.2011. 1994. Effects of Crocus sativus L. on the Crocetin prevents retinal degeneration ethanol-induced impairment of passive induced by oxidative and endoplasmic avoidance performances in mice. Biol reticulum stresses via inhibition of caspase Pharm Bulletin, 17: 217–221. activity. Eur J Pharmacol, 650: 110–119. Zhang Q, Powers Et, Nieva J, Huff Me, Zarrindast MR, Jafari-Sabet M, Rezayat M, Dendle Ma, Bieschke J, Glabe CG, Djahanguiri B, Rezayof A.2006. Eschenmoser A, Wentworth P, Lerner Ra. Involvement of NMDA receptors in 2004. Metabolite-initiated protein morphine state-dependent learning in mice. misfolding may trigger Alzheimer's Int J Neurosci, 116: 731–743, disease. Proc Natl Acad Sci U S A, 101: Ziaee Toktam; Bibi Marjan Razavi ; Hossein 4752-4757. Hosseinzadeh. 2014. Saffron Reduced Toxic Effects of its Constituent, Safranal, in Acute and Subacute Toxicities in Rats. Jundishapur J Nat Pharm Prod, 9:3-8.

AJP, Vol. 5, No. 5, Sep-Oct 2015 391