Bioactive Nutraceuticals and Dietary Supplements in

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Analgesic and Anti-Inflammatory Effects of Crocus sativus L. (Saffron) Bahareh Amin1, Hossein Hosseinzadeh2 1Department

of Pharmacology and Physiology, School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran; 2Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, IR Iran

O U T L I N E Introduction319 Chemical Composition

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Saffron Uses in Traditional Medicine

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Pharmacological Studies on the Biological Activity of Saffron

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Antinociceptive and Anti-Inflammatory Effects

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References322

INTRODUCTION

CHEMICAL COMPOSITION

Commercial saffron from the stigmas of the Crocus sativus flower (Iridaceae family) is the most expensive spice worldwide (Schmidt et al., 2007). This plant is a perennial bulbous, stemless herb cultivated in many areas of the Mediterranean region and principally in Iran. Iran is the largest producer of saffron and accounts for approximately 90% of the total world production in recent decades (Ghorbani, 2008; Schmidt et al., 2007). This review is mainly intended to provide a comprehensive review of the chemical composition, uses in folk medicine, and pharmacological actions of the plant, with a focus on the antinociceptive and antiinflammatory effects. We also discuss if Crocus sativus possesses antinociceptive activity through an experimental model of neuropathic pain. In the spinal cord, anti-inflammatory and antioxidant effects of saffron are evaluated. Finally, some potential mechanisms by which saffron and its active ingredients could relieve chronic pain are also discussed.

The color of saffron comes from water-soluble carotenoids, including crocetin (8,8′-diapocarotenedioic acid) and crocins (mono-, di-, and triglycosyl esters of crocetin; Alavizadeh & Hosseinzadeh, 2013; Gregory et al., 2005). Picrocrocin, a beta-d glucoside of safranal, is responsible for the bitter taste of saffron and is its second most abundant component (Alonso et al., 2001). Safranal (2,6,6-trimethyl-1,3-cyclohexadiene1-carboxaldehyde), a terpene aldehyde, the major volatile oil that comprises as much as 60–70% of the essential oil in the stigma, is most responsible for the distinctive aroma of this spice and is produced from dehydration of picrocrocin during the drying process (Lozano et al., 2000). Furthermore, saffron contains protein, moisture, fat, riboflavin and thiamine vitamins, minerals, crude fiber, and sugars, including starch, reducing sugars, pentosans, gums, pectin, and dextrins (Rios et al., 1996).

Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease http://dx.doi.org/10.1016/B978-0-12-411462-3.00033-3

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33. ANALGESIC AND ANTI-INFLAMMATORY EFFECTS OF CROCUS SATIVUS L. (SAFFRON)

SAFFRON USES IN TRADITIONAL MEDICINE Saffron has been used since ancient times as a spice for flavoring and coloring foods, perfumes, or dyes. Since time immemorial, it has been used in folk medicine for treating a wide range of disorders. Saffron is recommended as an aphrodisiac agent, anodyne, antidepressant, sedative, respiratory decongestant, anticatarrhal, expectorant, antispasmodic, eupeptic, stomachic, carminative, analgesic, and for relief of gingivitis and lumbar pain (Abdullaev & Espinosa-Aguirre, 2004; Hosseinzadeh and Nassiri-Asl, 2013; Zargari, 1990).

PHARMACOLOGICAL STUDIES ON THE BIOLOGICAL ACTIVITY OF SAFFRON The traditional uses of saffron are now supported by a number of pharmacological studies. Saffron extracts and/or active constituents have been identified to possess antioxidant (Hosseinzadeh et al., 2009), antitumor (Abdullaev, 2002), memory- and learning-enhancing (Abe & Saito, 2000; Hosseinzadeh et al., 2012; Papandreou et al., 2006), anticonvulsant (Hosseinzadeh et al., 2008), antianxiety (Hosseinzadeh and Noraei, 2009), antidepressant (Hosseinzadeh et al., 2003), and insulin resistance-reducing effects (Xi et al., 2007). Neuroprotective actions of saffron against cerebral ischemia-induced oxidative damage (Hosseinzadeh & Sadeghnia, 2005; Ochiai et al., 2007) and acrylamideinduced neuronal insult (Mehri et al., 2012) have also been reported.

ANTINOCICEPTIVE AND ANTIINFLAMMATORY EFFECTS Claudius Galenus, a prominent Roman physician and philosopher, described the details of a remedy prescribed for the relief of pains and swellings called ‘dark Olympic victor’s ointment.’ Saffron (6.67% W/V) was one of the main constituents of this ointment, said by Galenus to have an analgesic effect (Bartels et al., 2006). Acute administration of aqueous and ethanolic stigma extracts of saffron as well as safranal have shown antinociception in several models of antinociceptive tests in mice, namely the acetic acid visceral nociception and xylene-induced ear edema. Meanwhile, the number of writings in the acetic acid test was only partially inhibited by naloxone, suggesting that opioid receptors may play a small role and that other mechanisms contribute to a more important role in the antinociceptive activity of extracts (Hosseinzadeh &

Shariaty, 2007; Hosseinzadeh & Younesi, 2002). Crocin was reported to have an anti-inflammatory effect in some models of inflammation induction (Ma, 1998). Furthermore, the usefulness of saffron extracts and safranal in inflammatory conditions was shown in rat paw pain induced by formalin (Hosseinzadeh & Younesi, 2002). Arabian et al. (2009) reported that aqueous extract of saffron inhibited formalin-induced paw edema in the chronic but not acute phase of a formalin test. Meanwhile, a nonselective inhibitor of nitric oxide synthetize (NOS), L-NAME, potentiated the extract effect. In a study by Nagaki et al. (2003), intravenous injection of crocetin inhibited the LPS-induced aqueous flare elevation and partially prevented prostaglandin E2 (PGE2) induced aqueous flare elevation in rabbits. Trans-sodium crocetinate protected liver and kidney and lowered levels of tumor necrosis factor-α (TNF-α) in the liver and spleen in a rat model of hemorrhagic shock (Stennett & Gainer, 2004). In a recent study conducted on rats, hypertonic saline-induced corneal pain was attenuated by crocin. In addition, crocin increased morphine-induced antinociception not reversed by naloxone, suggesting again that the opioid receptors may not be involved in the analgesic action of this compound (Tamaddonfard & Hamzeh-Gooshchi, 2010). In a study by Xu et al. (2009), crocin inhibited the xyleneinduced ear edema in mice and carrageenan-induced paw edema as well as production of PGE2-induced lipopolysaccharide in rats. Tamaddonfard et al. (2012) demonstrated that the local paw edema and neutrophil infiltration induced by histamine were prevented by crocin. Recently, aqueous and methanolic extracts of petals showed anti-inflammatory effects in the carrageenan-induced rat paw edema (Kumar et al., 2012). Neuropathic pain is a chronic and disabling condition originating from damage or injury to the central nervous system (CNS) or peripheral nervous system (PNS) and is characterized by ongoing pain, allodynia, and hyperalgesia (Namaka et al., 2009). Peripheral neuropathic pain has been frequently observed in patients with diabetic neuropathy, lumbar disc syndrome, post-herpes infection, multiple sclerosis, traumatic spinal cord injury, stroke, and drug-induced states such as cancer chemotherapy or HIV therapy (Niv & Devor, 2006). Due to the complicated pathogenesis and undefined whole mechanisms involved, most patients are still unsatisfied (Niv & Devor, 2006). Many therapies, including antidepressants and certain anticonvulsants, are the first choices for treatment. However, these drugs produce only partial relief, and their high incidence of adverse effects limits their continuous usage (McCleane, 2003). Chronic constriction injury (CCI) of the sciatic nerve, developed by Bennett and Xie (1988), is one of the most

V. MECHANISMS OF ACTION OF NUTRACEUTICALS AND DIETARY SUPPLEMENTS

Antinociceptive and Anti-Inflammatory Effects

common models of mononeuropathy, which is induced by ligation to the sciatic nerve and mimics carpal tunnel syndrome in humans. In our previous study, CCI resulted in the development of paw mechano-tactile allodynia, cold-allodynia, and heat hyperalgesia. Mechanical allodynia, thermal hyperalgesia, and to a lesser extent thermal allodynia were attenuated dose dependently by a seven-day regimen of both aqueous and ethanolic extracts. Safranal also attenuated mechanical allodynia and thermal hyperalgesia of CCI animals in a dose-dependent manner. However, such effects were associated with sedation, as revealed by the decreased locomotor activity of rats in the open-field test, making it difficult to evaluate the antinociceptive effect of this compound (Amin & Hosseinzadeh, 2012). Existence investigations on the antinociceptive and anti-inflammatory effects of saffron extracts and/or active constituents in different experimental models are summarized in Table 33.1. Inflammatory processes, elevated levels of reactive oxygen species (ROS), and subsequently oxidative stress have been known as critical factors in the development of neuropathic pain via involvement in the central sensitization of the spinal cord (Chung, 2004; Vallejo et al., 2010). Applications of antioxidants that suppress cytokine elevations have been considered to be useful in the treatment of neuropathic pain (Comelli et al., 2008; Kandhare et al., 2012; Kanter, 2008; Li et al., 2007). Many beneficial effects of saffron, including antiallodynia and antihyperalgesia, have been mainly attributed to the antioxidant and anti-inflammatory properties of the main pharmacologically active ingredients. From different in vitro and in vivo studies of saffron extracts, crocetin, crocin, and safranal have been repeatedly shown to scavenge free radicals. Meanwhile, the highest antioxidant capacity was shown by crocin (Assimopoulou et al., 2005; Hosseinzadeh et al., 2009; Magesh et al., 2006; Rezaee and Hosseinzadeh, 2013). Crocin displayed a positive effect on the cognitive function via an antioxidant mechanism and inhibitory activity on amyloid-β aggregation (Papandreou et al., 2006). In a hemorrhagic shock model, mRNA expressions of TNF-α, interlukin 1β (IL-1β), and iNOS were inhibited by crocetin in the liver of rats (Yang et al., 2006). Crocin and crocetin reduced LPS-induced nitric oxide (NO) release, TNF-α, IL-1β, intracellular ROS, and nuclear factor kappa B (NF-κB) activation from cultured rat brain microglial cells (Nam et al., 2010). In a rat model of ischemic stroke, crocin significantly reduced malondialdehyde (MDA) as an index of lipid peroxidation and increased the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), in the ischemic cortex (Vakili et al., 2012). The possible mechanism of the protective effect

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of crocin against chemically induced colitis and colitis-related colon carcinogenesis in mice was also supported to occur partly by inhibiting inflammation and the mRNA expression of certain proinflammatory cytokines and inducible inflammatory enzymes (Kawabata et al., 2012). In another study, quinolinic acid-induced oxidative damage was inhibited by safranal in the hippocampus of rats (Sadeghnia et al., 2013). Our experimental results demonstrated that CCI increased spinal cord proinflammatory cytokines as well as oxidative stress, supporting the idea that inflammation and free radicals play a key role in the development of CCI-induced neuropathy (Leung & Cahill, 2010; Siniscalco et al., 2007). Both extracts of saffron decreased MDA levels and reduced glutathione (GSH), a key antioxidant enzyme, preventing damage caused by ROS such as free radicals and peroxides. Inflammatory cytokines (TNF-α and IL1-β) and (after a delay) IL-6 decreased in the spinal cord of CCI animals that received saffron extracts (unpublished data). However, it seems that multiple mechanisms participate in the neuroprotective effects of saffron and its components. Increased contents of glutamate and aspartate, major excitatory neurotransmitters, have been implicated in the pathogenesis of neuropathic pain (Kawamata & Omote, 1996). We previously reported that safranal caused a significant decrease in the concentration of glutamate and aspartate in the extracellular space of the hippocampus following systemic administration of kainic acid in rats (Hosseinzadeh et al., 2008). Saffron extracts and crocetin were capable of binding the PCP-binding side of the N-methyl-D-aspartate (NMDA) receptor and the sigma (1) receptor, whereas the crocins and picrocrocin were not effective, which could explain another neuroprotective effect of saffron (Lechtenberg et al., 2008). In a study by Berger et al. (2011), crocetin was demonstrated to be involved in the antagonistic effect of saffron’s ethanolic extract on the NMDA but not on the kainate receptors. Hence, GABA release and the GABA-synthesizing enzyme glutamic acid decarboxylase decrease following CCI of the sciatic nerve (Dickenson et al., 1997). Safranal, via activation of the benzodiazepine-binding sites of the GABAA-receptor complex, displayed an antiabsence seizure activity in rats (Hosseinzadeh and Sadeghnia, 2007). Consequently, it seems that saffron may be a promising option as either an alternative or an adjunctive therapy in neuropathic pain through modulating immune response and oxidative stress in the spinal cord. However, further studies are needed to elucidate the exact mechanism of the actions underlying the antiallodynia and antihyperalgesia effects of saffron and its bioactive constituents.


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TABLE 33.1 The Effect of Different Doses of C. sativus Extracts and Its Bioactive Constituents on Various Nociceptive and Inflammatory Experimental Animal Models Part used

Method

Dose

Effect

Reference

Aqueous petal extract Ethanolic petal extract

Hot plate test in mice

1.4, 2.5, 3.6 g/kg, i.p. 0.8, 3.2, 5.6 g/kg, i.p.

No effect

Hosseinzadeh & Younesi, 2002

Aqueous stigma extract Ethanolic stigma extract


0.32, 0.56, 0.8 g/kg, i.p. 0.8, 1.4 and 2 g/kg, i.p.

No effect

Hosseinzadeh & Younesi, 2002; Hosseinzadeh & Shariaty, 2007

Safranal


0.5 ml/kg, i.p.

Increased the latency time

Hosseinzadeh & Shariaty, 2007

Crocins

Picryl chloride in rats

200 mg/kg, intragastric (i.g.)

Inhibited contact dermatitis

Ma, 1998

Crocins

Xylene induced ear edema 500 mg/kg, i.g. in mice

Reduced edema of ear

Ma, 1998; Xu et al., 2009


Xylene induced ear edema 0.56 g/kg, i.p. in mice 1.4 g/kg, i.p.

Reduced edema of ear

Hosseinzadeh & Younesi, 2002

Crocetin

LPS-induced aqueous flare elevation in rats and PGE2-induced aqueous flare elevation in rabbits

3–300 μg/kg, i.v.

Inhibited LPS-induced aqueous flare elevation; and partially prevented PGE2-induced aqueous flare elevation

Nagaki et al., 2003

Aqueous petal extract Ethanolic petal extract

Formalin test in mice

2.5, 3.6 g/kg, i.p. 1.6, 3.2 g/kg, i.p.

No effect

Arbabian et al., 2009; Hosseinzadeh & Younesi, 2002



Safranal


Crocins

Arbabian et al., 2009; Hosseinzadeh & Younesi, 2002 0.025, 0.05 ml/kg, i.p.

Reduced hind paw edema

Hosseinzadeh & Shariaty, 2007

Carrageenan and fresh egg 50 mg/kg, i.g, white in rats

Reduced hind paw edema

Ma, 1998; Xu et al., 2009

Aqueous petal extract Ethanolic petal extract Aqueous stigma extract Ethanolic stigma extract Safranal Crocins

Acetic acid-induced writhing test in mice

Reduced the number of abdominal constrictions

Hosseinzadeh & Younesi, 2002; Hosseinzadeh & Shariaty, 2007; Ma, 1998

Crocin

Hypertonic saline-induced 12.5, 25, 50 mg, ic.v corneal pain in rats 50, 100, 200 mg/kg, i.p.

Attenuated pain

Tamaddonfard & Hamzeh-Gooshchi, 2010

Aqueous stigma extract Ethanolic stigma extract Safranal Crocin

Sciatic nerve chronic constriction injury in rats

200 mg/kg, i.p., 200 mg/kg, i.p., 0.05 and 0.1 mg/kg, i.p. 12.5,25, 50 mg/kg, i.p.

Attenuated mechanical allodynia, cold allodynia, thermal hyperalgesia

Amin & Hosseinzadeh, 2012

Crocin

Subcutaneous injection of histamine in rats

100 and 200 mg/kg, i.p.

Reduced local paw edema induced by histamine

Tamaddonfard et al., 2012

Aqueous petal extract Methanolic petal extract

Carrageenan test in rats

400 mg/kg

Reduced edema in carrageenan induced paw edema

Kumar et al., 2012

1.4, 2.5, 3.6 g/kg, i.p. 0.8, 3.2, 5.6 g/kg, i.p. 0.32, 0.56, 0.8 g/kg, i.p. 0.8, 1.4, 2 g/kg, i.p. 0.1, 0.3, 0.5 ml/kg, i.p. 50 mg/kg, i.g.

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No effect

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