Saffron) and Its Constituents on Nervous System: a Review
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Review Article The effects of Crocus sativus (saffron) 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 crocin, picrocrocin and safranal. 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 carotenoids, α-crocetin and glycoside 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 lycopene and zeaxanthin 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 retinal 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 oxygen 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 isomer but cis-crocetin and its glycosides 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). carotenoid 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-carotene, beta-carotene, glycosylated carotenoids