Constituents of Saffron (Crocus Sativus L.) As Potential Candidates for the Treatment of Anxiety Disorders and Schizophrenia
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molecules Review Constituents of Saffron (Crocus sativus L.) as Potential Candidates for the Treatment of Anxiety Disorders and Schizophrenia Nikolaos Pitsikas Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Thessaly, Panepistimiou 3 (Biopolis), Larissa 41500, Greece; [email protected]; Tel.: +30-2410-685-535 Academic Editors: Maria Z. Tsimidou and Petros A. Tarantilis Received: 8 December 2015 ; Accepted: 29 February 2016 ; Published: 2 March 2016 Abstract: Anxiety disorders and schizophrenia are common public health issues. The dried stigma of the plant Crocus sativus L., (C. sativus) commonly known as saffron are used in folk medicine for various purposes. Several lines of evidence suggest that C. sativus, crocins and safranal are implicated in anxiety and schizophrenia. Here, I intend to critically review advances in research of these emerging molecules for the treatment of anxiety and schizophrenia, discuss their advantages over currently used anxiolytics and neuroleptics, as well remaining challenges. Current analysis shows that C. sativus and its components might be a promising class of compounds for the treatment of the above mentioned psychiatric diseases. Keywords: Crocus sativus L.; anxiety; stress; schizophrenia 1. Introduction Crocus sativus L. (C. sativus), is a perennial herb member of the Iridaceae family, the line of Liliaceae. This plant is cultivated in many countries such as Azerbaijan, China, France, Greece, Egypt, India, Iran, Israel, Italy, Mexico, Morocco, Spain and Turkey. Its product is the well-known spice called saffron. Saffron, in filaments, is the dried dark-red stigmas of C. sativus flower [1]. One stigma of saffron weighs about 2 mg and each flower has three stigmata; 150,000 flowers must be carefully picked one by one to obtain 1 kg of spice. Saffron has a distinct colour, flavour and odour. It is used both as a spice for flavouring and colouring food preparations, and as a perfume. The stigmas of it are also used in folk medicine as an anticatarrhal, eupeptic, antispasmodic, expectorant, emmenagogue and nerve sedative (for review see [2]). Further, saffron has widely been used in Persian traditional medicine for memory problems [3]. The present review was designed to critically assess the role played by C. sativus and its active constituents in anxiety and schizophrenia since the current pharmacotherapy for both these diseases is not satisfactory. 2. Chemistry of C. sativus Chemical analysis of C. sativus stigmas has shown the presence of about 150 volatile and non-volatile compounds. Fewer than 50 constituents, however, have been identified so far [4]. The volatiles consist of more than 34 components that are terpenes, terpene alcohols and their esters among which safranal is the main component. Non-volatile compounds comprise crocins, crocetin, picrocrocin and flavonoids (quercetin and kaempferol) [5]. Molecules 2016, 21, 303; doi:10.3390/molecules21030303 www.mdpi.com/journal/molecules Molecules 2016, 21, 303 2 of 11 Molecules 2016, 21, 303 2 of 10 In particular,In particular, crocins, crocins, glucosyl glucosyl esters esters of crocetin, of crocetin, are are water-soluble water-soluble carotenoidscarotenoids and and are are responsible responsible for saffron’sfor saffron’s characteristic characteristic colour. colour. Picrocrocin, Picrocrocin, glycoside glycoside of safranal,of safranal, is responsibleis responsible for for the the bitterbitter taste of the spiceof andthe spice is the and precursor is the precursor of safranal. of safranal. Safranal, Safr theanal, main the main component component of theof the distilled distilled essential essential oil, is a monoterpeneoil, is a monoterpene aldehyde, aldehyde, responsible responsible for its for characteristic its characteristic aroma aroma [6 [6,7].,7]. InIn Figure 1 thethe molecular molecular structurestructure of C. sativus of C. sativuscomponents components crocin crocin and and saffranal saffranal is is illustrated. illustrated. FigureFigure 1. Molecular 1. Molecular structures structures of C. of sativusC. sativuscomponents componentscrocin crocin and safranal. safranal. 3. Effects of C. sativus and Its Constituents on Anxiety 3. Effects of C. sativus and Its Constituents on Anxiety Anxiety may be interpreted as an emotional anticipation of an aversive situation and is reflected Anxietyby species-specific may be interpreted behavioural as anfear emotional responses anticipationto stressful and of anthreatening aversive stimuli, situation characteristic and is reflected for by species-specificindividual trait behavioural anxiety. Anxiety fear responses disorders toinclud stressfuling generalized and threatening anxiety disorder stimuli, characteristic(GAD), specificfor individualand traitsocial anxiety. phobias, Anxiety post-traumatic disorders stress including disorder (PTSD), generalized obsessive-compulsive anxiety disorder disorder (GAD), (OCD) specific and and social phobias,panic disorder post-traumatic are a major stress public disorder health issue (PTSD), worldwide. obsessive-compulsive disorder (OCD) and panic disorder areTo a majordate, anxiety public disorders health issue have worldwide. been treated with medications that target γ-aminobutyric acid To(GABA) date, anxiety and serotonergic disorders neurotransmission, have been treated like with benz medicationsodiazepines, partial that targetagonistsγ -aminobutyricof the serotonergic acid (GABA)5-HT and1A serotonergic receptor and neurotransmission,selective serotonin re-uptake like benzodiazepines, inhibitors (SSRIs). partial Some agonistsforms of anxiety, of the serotonergic however, are relatively resistant to treatment with these agents [8,9]. In addition, either benzodiazepines or 5-HT receptor and selective serotonin re-uptake inhibitors (SSRIs). Some forms of anxiety, however, 1ASSRIs can be associated with severe side effects, such as sedation, memory deficits, dependence and are relatively resistant to treatment with these agents [8,9]. In addition, either benzodiazepines or withdrawal, sexual dysfunction and weight gain. Further, the 5-HT1A receptor partial agonist buspirone SSRIs canhas a be somewhat associated limited with use. severe Although side it effects, is generally such well as tolerated sedation, with memory few side deficits, effects, it dependence has lower and withdrawal,efficacy and sexual its onset dysfunction of action is slower and weight than pr gain.evious Further,drugs such the as 5-HT the benzodiazepines1A receptor partial [10]. Thus, agonist buspironethere has is an a somewhat urgent need limited to develop use. alternative Although treatment it is generally strategies well [11]. tolerated with few side effects, it has lower efficacy and its onset of action is slower than previous drugs such as the benzodiazepines [10]. Thus, there3.1. Preclinical is an urgent Studies need to develop alternative treatment strategies [11]. An overview of the preclinical literature regarding the effects of C. sativus and its constituents 3.1. Preclinicalon anxiety Studies is provided in Table 1. Experimental evidence indicated that crocins displayed an Ananxiolytic-like overview of effect the preclinical in procedures literature assessing regarding anxiety in the rats effects [12,13]. of Particularly,C. sativus and in the its light/dark constituents test, on anxietyadministration is provided in of Table 50 1mg/kg. Experimental crocins, similarly evidence to indicated the reference that crocinscompound displayed diazepam an anxiolytic-like(1.5 mg/kg), increased the time to enter the dark compartment, did not affect the number of transitions between effect in procedures assessing anxiety in rats [12,13]. Particularly, in the light/dark test, administration the light and the dark chamber of the apparatus and prolonged the time spent in the lit compartment of 50 mg/kgof the light/dark crocins, box similarly [12]. In to addition, the reference crocins ( compound30 and 50 mg/kg) diazepam were found (1.5 mg/kg), to reduce increasedcompulsive the time tobehaviour enter the (excessive dark compartment, grooming) induced did by not the affect serotonergic the number 5-HT2c receptor of transitions agonist 1-(3-chlorophenyl) between the light and thepiperazine dark chamber hydrochloride of the apparatus (mCPP) (0.6 and mg/kg) prolonged [13]. Interestingly, the time spent crocins, in theat any lit dose compartment tested, did ofnot the light/darkalter box rats’ [ 12locomotor]. In addition, activity. crocins Collectively, (30 and the 50 result mg/kg)s of the were above found described to reduce studies compulsive suggest that behaviour these (excessiveactive grooming) constituents induced of C. sativus by the induce serotonergic anxiolytic-like 5-HT2c behaviourreceptor agonist in the rat 1-(3-chlorophenyl)piperazine and their anxiolytic effects hydrochloridecannot be (mCPP) attributed (0.6 to mg/kg)changes in [13 locomotor]. Interestingly, activity [12,13]. crocins, at any dose tested, did not alter rats’ locomotor activity. Collectively, the results of the above described studies suggest that these active constituents of C. sativus induce anxiolytic-like behaviour in the rat and their anxiolytic effects cannot be attributed to changes in locomotor activity [12,13]. Molecules 2016, 21, 303 3 of 11 Table 1. Effects of Crocus sativus L., and its constituents on animal models of anxiety disorders and schizophrenia. Species Agent Dose Range Route Behavioural Test Effect Ref. Light/dark Anxiolytic-like (50 mg/kg) effect Rat Crocins 15,