Saffron or Crocus sativus L. (C. sativus) has been widely used as a medicinal plant to promote human health, especially in Asia. The main components of saffron are crocin, picrocrocin and safranal. Saffron has been suggested to be effective in the treatment of a wide range of disorders including coronary artery diseases, hypertension, stomach disorders, dysmenorrhea and learning and memory impairments. In addition, different studies have indicated that saffron has anti-inflammatory, anti-atherosclerotic, antigenotoxic and cytotoxic activities.
Antitussive effects of stigmas and petals of C. sativus and its components, safranal and crocin have also been demonstrated. The anticonvulsant and anti-Alzheimer properties of saffron extract were shown in human and animal studies. The efﬁcacy of C. sativusin the treatment of mild to 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.
Crocus sativus L (C. sativus), commonly known as saffron, is a small perennial plant belonging to the family of Iridaceas. This plant is cultivated in many countries including Iran, Afghanistan, Turkey and Spain (Abdullaev, 1993 ▶). The stigmas of C. sativus are known to contain carotenoids, α-crocetin and glycoside crocin (responsible for saffron yellow color) and picrocrocin, the aglyconesafranal (responsible for saffron aroma) (Fernández and Pandalai, 2004 ▶; Champalab et al., 2011), the antioxidant carotenoids lycopene and zeaxanthin and vitamin B2(Vijaya Bhargava, 2011).
Table of Contents
C. sativus constituents
More than 150 compounds have been identified in saffron stigma including colored carotenoids (e.g. crocetin and crocins as glycosidic derivatives), colorless monoterpene aldehydes, volatile agents (e.g. safranal and picrocrocin which are the bitter components), etc. (Bathaie and Mousavi, 2010 ▶).
In Iranian folk medicine, C. sativus had been used as an anticonvulsant herb (Khosravan, 2002 ▶). Experimental studies also confirmed saffron anticonvulsant effects in rats and mice (Sunanda et al., 2014▶; Khosravan, 2002 ▶). Saffron at the doses of 400 and 800 mg/kg showed a significant antiepileptic activity in pentylenetetrazole (PTZ)-induced seizure model in a dose-dependent manner.
Administration of saffron 30 mg/day (15 mg twice daily) was found to be as effective as donepezil for treatment of mild-to-moderate AD in the subjects of 55 years and older (Akhondzadeh et al., 2010a ▶ ).
Antidepressant and anti- schizophrenia effects
In a randomized and double-blind clinical trial study, saffron supplementation statistically improved the mood of subjects compared to the placebo group. For six weeks, 30 mg/day of saffron was given and subjects were evaluated based on the Hamilton Depression Rating Scale (HAM-D) (Akhondzadeh et al., 2005 ▶).
Short-term administration of saffron (30 mg/day) capsules for six weeks was also shown to be as effective as ﬂuoxetine (40 mg/day) in improving depression symptoms in patients who were suffering from major depressive disorder (MDD) after undergoing a percutaneous coronary intervention (Shahmansouri et al., 2014 ▶).
Saffron and its components (mainly crocin, crocetin, and safranal) have been used in animal models with neurodegenerative diseases (Ochiai et al., 2007 ▶; Purushothuman et al., 2013 ▶). Crocin and safranal have inhibitory effect on ﬁbrillation of apo alpha-lactalbumin (a-alpha-LA), under amyloidogenic conditions which crocin was found to be more effective than safranal. Formation of toxic amyloid structures is related with various neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases (Ebrahim-Habibi et al. 2010 ▶).
Effects of C. sativus on oxidative damages and neurotoxicity
Treatment with saffron extract (5 and 25 mg/ml) and crocin (10 and 50 μM) could decrease the neurotoxic effect of glucose in PC12 cells. The results showed that glucose (13.5 and 27 mg/ml) reduced PC12 cells viability while cell death was reduced by saffron and crocin pretreatment (Mousavi et al., 2010▶).
In addition, crocin increased the activity of SOD and glutathione peroxidase (GPx) and remarkably reduced malondialdehyde (MDA) content in the ischemic cortex in rat model of ischemic stroke (Vakili et al., 2013▶).
Effects of C. sativus on neuronal injury and apoptosis
Crocin (30, 60 and 120 mg/kg) showed protective effect against ischemia/reperfusion injury and cerebral edema in a rat model of stroke and decreased infarct volume. Administration of crocin (60 mg/kg), one hour before, or one hour after the induction of ischemia, reduced brain edema (Vakili et al., 2013 ▶).
The neuroprotective effects of crocetin in the brain injury in animal studies have been suggested to be related to its ability to inhibit apoptosis at early stages of the injury and its ability to promote angiogenesis at the subacute stage as directed by higher expression levels of vascular endothelial growth factor receptor-2 (VEGFR-2) and serum response factor (SRF) (Bie et al., 2011 ▶).
Effects of C. sativus on neuroinflammation
Crocin inhibited syncytin-1 and nitric oxide (NO)-induced astrocyte and oligodendrocyte cytotoxicity (Christensen, 2005 ▶) and reduced neuropathology in experimental autoimmune encephalomyelitis (EAE) with signiﬁcantly less neurological impairments.
Administration of crocin on day 7 post-EAE induction, suppressed ER stress and inflammatory gene expression in the spinal cord and also reduced the expression of ER stress genes XBP-1/s (Deslauriers et al., 2011 ▶).
C. sativus and the brain neurotransmitters
Ettehadi et al. (2013) ▶ showed that the aqueous extract of saffron (50, 100, 150 and 250 mg/kg, i.p.) increased brain dopamine concentration in a dose-dependent manner. Moreover, the extract had no effect on brain serotonin or norepinephrine concentration. In addition, the results showed that the aqueous extract of saffron especially at the dose of 250 mg/kg triggered and increased the production of important neurotransmitters including dopamine and glutamate in rat brain (Ettehadi et al., 2013 ▶).
C. sativus and opioids system
The effects of C. sativus on opioid system
|C. Sativusor its constituents||Dose||Results||References|
|Sa ﬀ ron||150 and 450 mg/kg||Improved learning and memory impairment induced by morphine||Naghibi et al., 2012|
|Sa ﬀ ron||Aqueous (80, 160, 320 mg/kg) and ethanolic (400 and 800 mg/kg) extract||Reduced naloxone precipitated jumping||Ghoshooni et al., 2011; shams et al., 2009|
|Crocin||200 and 600 mg/kg||Reduced withdrawal sign without reducing locomotor activity||Amin and hosseinzadeh 2012|
|C. sativusstigma||Alcohol extract (5 and 10 µg/rat)||Decrease in the time spent in drug paired side||Ghoshooni et al., 2011|
|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 brains and increased the release of glutamate only in dose 250||Ettehadi et al., 2013|
Anti-oxidant and anti-inflammatory effects of the extracts of C. sativus and its constituents (crocetin, crocins, safranal) implies saffron therapeutic potential for various nervous system disorders.
Based on the literature, beneficial effects of the plant and its components on neurodegenerative disorders such as Alzheimer and Parkinson’s disease are mainly due to their interactions with cholinergic, dopaminergic and glutamatergic systems. It is assumed that saffron anticonvulsant and analgesic properties and its effects on morphine withdrawal and rewarding properties of morphine might be due to an interaction between saffron, GABA and opioid system.
According to human and animal studies, saffron and its constituents have been shown to be effective in the treatment of mild to moderate depression which may be because of an interaction with the serotonin and noradrenaline system. However, to have a detailed perspective of saffron effects on nervous system, more mechanistic investigations are highly advised.