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Black Cumin (Nigella sativa) and Its Active Constituent, Thymoquinone: An Overview on the Analgesic and Anti-inflammatory Effects

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For many centuries, seeds of Nigella sativa (black cumin), a dicotyledon of the Ranunculaceae family, have been used as a seasoning spice and food additive in the Middle East and Mediterranean areas. Traditionally, the plant is used for asthma, hypertension, diabetes, inflammation, cough, bronchitis, headache, eczema, fever, dizziness, and gastrointestinal disturbances. The literature regarding the biological activities of seeds of this plant is extensive, citing bronchodilative, anti-inflammatory, antinociceptive, antibacterial, hypotensive, hypolipidemic, cytotoxic, antidiabetic, and hepatoprotective effects. The active ingredients of N. sativa are mainly concentrated in the fixed or essential oil of seeds, which are responsible for most health benefits. This review will provide all updated reported activities of this plant with an emphasis on the antinociceptive and anti-inflammatory effects. Results of various studies have demonstrated that the oil, extracts, and their active ingredients, in particular, thymoquinone, possess antinociceptive and anti-inflammatory effects, supporting the common folk perception of N. Sativa as a potent analgesic and anti-inflammatory agent. Many protective properties are attributed to reproducible radical scavenging activity as well as an interaction with numerous molecular targets involved in inflammation, including proinflammatory enzymes and cytokines. However, there is a need for further investigations to find out the precise mechanisms responsible for the antinociceptive and anti-inflammatory effects of this plant and its active constituents. Georg Thieme Verlag KG Stuttgart · New York.
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Introduction
!
The use of medicinal plants in various ailments
dates back to the earliest years of manʼsevolution
[1]. Nigella sativa L. (Ranunculaceae) is an indige-
nous herbaceous plant native to Southwest Asia
including Iran, India, and Pakistan. The plant
grows to a maximum height of about 4070 cm
and has finely divided foliage and pale blue and
white flowers. From the fruit capsules, many
small caraway-type black seeds are produced
(length: 2.5 to 3.5 mm and width: 1.5 to 2 mm).
In different languages the plant is known by vari-
ous names, e.g., black cumin, black seed, black-
caraway (English), Habbah Al-Sauda, seed of
blessing (Arabic), chernushka (Russian), çörek otu
(Turkish), and Cyah-daneh in Persian. For thou-
sands of years, the seeds of this plant have been
used as a spice and additive in bread, cookies,
and other dishes in many Asian and Eastern coun-
tries [2]. Therapeutic benefits of black cumin and
its active ingredients have been demonstrated in
many investigations [35].
Chemical Composition
!
N. sativa seeds contain various compositions in-
cluding moisture, oil, proteins (eight of the nine
essential amino acids), carbohydrates, vitamins,
and minerals [6, 7]. The percentage of ingredients
varies with the geographic distribution, time of
harvest, and cultivation methods [8].
In a study by Cheikh-Rouhou et al. comparing Tu-
nisian and Iranian varieties for their quality at-
tributes, the Tunisian variety contained 8.65,
28.48, 26.7, 4.86, and 40.0% of moisture, oil, pro-
teins, ash, and carbohydrates, respectively, while
analysis of the Iranian variety showed 4.08,
40.35, 22.6, 4.41, and 32.7% of the respective at-
tributes [9].
Black cumin seed is composed of fixed (stable)
and essential (volatile) oil responsible for many
Abstract
!
For many centuries, seeds of Nigella sativa (black
cumin), a dicotyledon of the Ranunculaceae fam-
ily, have been used as a seasoning spice and food
additive in the Middle East and Mediterranean
areas. Traditionally, the plant is used for asthma,
hypertension, diabetes, inflammation, cough,
bronchitis, headache, eczema, fever, dizziness,
and gastrointestinal disturbances. The literature
regarding the biological activities of seeds of this
plant is extensive, citing bronchodilative, anti-in-
flammatory, antinociceptive, antibacterial, hypo-
tensive, hypolipidemic, cytotoxic, antidiabetic,
and hepatoprotective effects. The active ingre-
dients of N. sativa are mainly concentrated in the
fixed or essential oil of seeds, which are responsi-
ble for most health benefits. This review will pro-
vide all updated reported activities of this plant
with an emphasis on the antinociceptive and
anti-inflammatory effects. Results of various
studies have demonstrated that the oil, extracts,
and their active ingredients, in particular, thymo-
quinone, possess antinociceptive and anti-inflam-
matory effects, supporting the common folk per-
ception of N. Sativa as a potent analgesic and anti-
inflammatory agent. Many protective properties
are attributed to reproducible radical scavenging
activity as well as an interaction with numerous
molecular targets involved in inflammation, in-
cluding proinflammatory enzymes and cytokines.
However, there is a need for further investigations
to find out the precise mechanisms responsible
for the antinociceptive and anti-inflammatory ef-
fects of this plant and its active constituents.
Black Cumin (Nigella sativa) and Its Active Constituent,
Thymoquinone: An Overview on the Analgesic and
Anti-inflammatory Effects
Authors Bahareh Amin1, Hossein Hosseinzadeh 2
Affiliations 1Department of Pharmacology and Physiology, School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
2Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad
University of Medical Sciences, Mashhad, Iran
Key words
l
"Nigella sativa
l
"Ranunculaceae
l
"thymoquinone
l
"analgesia activity
l
"antiinflammatory effect
received Nov. 22, 2014
revised June 29, 2015
accepted July 16, 2015
Bibliography
DOI http://dx.doi.org/
10.1055/s-0035-1557838
Published online
Planta Med © Georg Thieme
Verlag KG Stuttgart · New York ·
ISSN 00320943
Correspondence
Prof. Dr. Hossein Hosseinzadeh
Pharmaceutical Research Center
School of Pharmacy
Mashhad University of Medical
Sciences
Department of Pharmaco-
dynamics and Toxicology
136591775 Mashhad, I. R.
Iran
Phone: + 98 51 38 81 90 42
Fax:+ 985138823251
hosseinzadehh@mums.ac.ir
Amin B, Hosseinzadeh H. Black Cumin (NigellaPlanta Med
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beneficial effects attributed to N. sativa. Fixed oil contains appre-
ciable quantities of unsaturated fatty acids (linoleic, oleic, and in-
olenic acids) as well as saturated fatty acids in minor amounts
(arachidonic and eicosenoic acids). Dihomo-γ-lionoleic acid is a
powerful antioxidant, which exists in the fixed oil of seeds [3,
10]. Besides the fatty acid profile, it also consists of considerable
quantities of vitamin E (tocopherol α,β,andγ), retinol (vitamin
A), carotenoids (β-carotene), and thymoquinone (2-isopropyl-5-
methyl-1,4-benzoquinone). Fat-soluble vitamins comprise more
than 0.2% of the total oil content [11, 12].
Other ingredients of N. sativa include minerals such as potassi-
um, phosphorus, calcium, and iron, in greater quantities, as well
as zinc, magnesium, manganese, selenium, and copper in fewer
amounts. Alkaloids such as nigellimine, nigellidine, and nigelli-
cine are also present in trace amounts [1113]. Black cumin has
been known to contain considerable quantities of phytosterols
including β-sitosterol, avenasterol, stigmasterol, campesterol,
and lanosterol [1416].
Moreover, essential oil extracted from black cumin is of function-
al importance because of its rich volatiles, such as 18.424 % thy-
moquinone (TQ), 46% monoterpenes including p-cymene, α-
pinene, thymol (THY), dithymoquinone (DTQ, nigellone), and
thymohydroquinone (THQ) [1719]. The general chemical com-
position of N. sativa seeds has been presented in l
"Table 1 [6
8,1017]. Photodimerization of thymoquinone as a consequence
of exposure to sunlight during separation and extraction of the
quinones from the seed produces dithymoquinone. Among the
components isolated from the volatile oil of N. sativa, TQ has been
demonstrated to be the principal active ingredient [11, 20].
The chemical structure of main ingredients of N. sativa oil includ-
ing thymoquinone, dithymquinone, thymohydroquinone, p-
cymene, and thymol is shown in l
"Fig. 1.
Traditional Uses of Nigella sativa
!
Traditional uses of this amazing herb originate from the ancient
Egyptians, Greeks, and Romans. Black seed is referred to by the
Islamic prophet Mohammed as having healing powers for every
disease except death. N. sativa has been advocated by Ibn Sina
(Avicenna), the most famous physician and philosopher of the Is-
lamic world, as the bodyʼs energizing compound and as a remedy
Fig. 1 Chemical structure of the active ingredients
of oil of N. sativa L. seeds.
Table 1 The general chemical composition of N. sativa seeds [68, 1117].
Constituents Chemical composition % Range (w/w)
Oil Fixed oil Linoleic acid (Omega-6), Oleic acid, Palmitoleic acid Linolenic acid (Omega-3), Myristoleic acid, Diho-
molionolenic acid, Stearic acid, Eicosadienoic acid, Myristic acid, Arachidic acid, Behanic acid, Sterols
(β-sitosterol, avenasterol, stigmasterol, campesterol and lanosterol), Tocopherols (α,β,and γ) Thymo -
quinone, Retinol (vitamin A), Carotenoids (β-carotene)
2238%
Volatile oil Thymoquinone, p-Cymene, Carvacol, α-Pinene, β-Pinene, Longifolene, t-Anethole Thymol, Thymo-
hydroquinone, Dithymoquinone (nigellone)
0.401.50%
Protein Glutamic acid, Arginine, Aspartic acid, Leucine, Glycine, Valine, Lysine, Threonine, Phenylalanine Iso-
leucine, Histidine, Methionine
20.831.2%
Carbohydrate Glucose, Rhamnose, Xylose,Arabinose 24.940%
Minerals Calcium, Phosphorus, Iron, Potassium, Sodium, Zinc, Magnesium, Manganese, Copper, Selenium 3.77%
Saponins α-Hederin (melanthin), Hederagenin (melanthigenin) 0.013%
Alkaloids Nigelicine, Nigellimine, Nigellidine 0.01%
Other Vitamins Vitamin A, Thiamin, Riboflavin, Pyridoxine, Niacin, Folacin, Vitamin C 14%
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for fever, headaches, toothaches, and common colds. It was also
recommended as a soothing agent for skin disorders, wounds,
and external irritations [21]. According to the Holy Bible, black
seed is described as the melanthion by Hippocrates and Dioscor-
ides and as the Gith by Pliny [22].
In folklore medicine, the seeds and oil of N. sativa have been fre-
quently prescribed as a natural remedy for a diverse range of dis-
eases, such as, fever, cough, nasal congestion, bronchitis, asthma,
dyspnea, hypertension, diabetes, inflammation, milk production,
eczema, dizziness, and gastrointestinal disturbances. Its use in
pain conditions such as headaches, toothaches, and back pain
has also been recommended [23, 24].
Pharmacological Studies on the Biological Activities
!
N. sativa and its main active constituent TQ have been attributed
to numerous pharmacological activities [25]. Up to now, cyto-
toxic [26,27], antioxidant [2831], immune enhancement [32,
33], gastroprotective, hepatoprotective [34,35], antitussive [36],
hypolipidemic, and cardioprotective effects [3739], increased
milk production [40], hypoglycemic [41], hypotensive [42], and
antimicrobial [43,44] effects have been demonstrated. In addi-
tion, beneficial effects of N. Sativa and thymoquinone on convul-
sions [45, 46], depression [47], menʼs infertility [48], memory im-
provement [49], nociception, and inflammation [50, 51] have
been discussed.
Antinociceptive activity
Early work by Abdel-Fattah and coworkers demonstrated that
oral administration of N. sativa oil (50400 mg/kg) dose-depen-
dently attenuated the nociceptive responses caused by the acute
nociceptive stimuli such as the hot-plate test (thermal stimulus),
tail-pinch test (mechanical stimulus), and the early phase of the
formalin test (chemical stimulus). It also suppressed inflamma-
tory nociception induced by acetic acid writhing without affect-
ing spontaneous motor activity in mice. In that study, the system-
ic administration (2.510 mg/kg, p. o. and 16 mg/kg, i. p.) and
the intracerebroventricular (i.c. v.) injection (14 mg/kg) of thy-
moquinone to mice attenuated the response in not only the early
phase, but also the late phase of the formalin test. The authors
suggested that N. sativa oil and TQ produce antinociceptive ef-
fects through indirect activation of the supraspinal µ-1 and κ-
opioid, but not the δ-opioid receptor subtypes. However, none of
these receptor subtypes was implicated in the antinociceptive ef-
fect of TQ in the late phase of the formalin test [52].
In addition, Al Nagger et al. studied the neuropharmacological
activity of N. sativa extracts. Aqueous and methanolic extracts of
black cumin were found to elicit thermal and mechanical ant i-hy-
peralgesic effects in the hot-plate and Randall-Selitto tests, re-
spectively [53]. In another study, the aqueous extract of N. sativa
(500 mg/kg, p. o.) significantly increased the hot plate reaction
time in mice [54]. In an investigation by De Sousa and coworkers,
thymoquinone and its para-benzoquinone analogues showed a
significant reduction in the paw licking time of animals in two
phases of the formalin test [55]. In a recent randomized control
trial study on mice (30 animals in each group), the ethanolic ex-
tract of N. sativa showed antinociceptive effects against an acetic
acid-induced writhing test [56].
Neurotransmitters, such as gamma aminobutyric acid (GABA),
have an important role in descending inhibitory pathways of pain
[57, 58]. An increase in GABAergic tone has been demonstrated in
the anxiolytic and anticonvulsant activities of extracts as well as
TQ [45,59, 60].
Another potential antinociceptive effect of thymoquinone might
be through intervening in the serotonin/5-hydroxytriptamine (5-
HT) pathway. The role of 5-HT and norepinephrine via descend-
ing inhibitory pathways has also been demonstrated in the mod-
ulation of pain [61, 62]. Fixed oil of N. sativa (0.1 mL/kg/day) for
four weeks elicited antidepressant activity through the increased
brain 5-HT levels and decreased 5-HT turnover [47].
Anti-inflammatory activity
The volatile oil (0.66 ml and 1.55 mL/kg, i.p.) of N. sativa and thy-
moquinone (0.5, 1.0, 5 mg/kg, i. p.) exhibited a dose-dependent
anti-inflammatory effect against carrageenan-induced rat hind
paw edema and cotton seed pellet granuloma comparable to the
reference drug indomethacin (3 mg/kg, i. p.) [63]. Similarly, Al-
Ghamdi and coworkers demonstrated that the aqueous extract
of N. sativa possesses an anti-inflammatory action in carra-
geenan-induced paw edema similar to 100 mg/kg aspirin; how-
ever, it had no antipyretic activity on yeast-induced pyrexia [54].
In another study by Hajhashemi et al. as well as Ghannadi et al.,
both oral and intraperitoneal administration of polyphenols ex-
tracted from N. sativa as well as essential oil (200, 400, and
800 µL/kg) containing p-cymene (37.3%) and thymoquinone
(13.7%) suppressed the early and late phases of the formalin test,
acetic acid-induced writhing in mice, carrageenan-induced paw
edema, and croton oil-induced ear edema in rats. The authors re-
ported that treatment with naloxone failed to reverse the analge-
sic activities of both the polyphenols and essential oil [50, 64].
The methanolic extracts of different germination phases of
N. sativa showed significant anti-inflammatory and antinocicep-
tive effects in kaolin-induced rat paw edema and hot-plate tests,
respectively, throughout the duration of the study (1, 3, 6, and
18 h after the injection of kaolin). The highest effect was ob-
served from the 5th day to the 11th day of germination [65].
l
"Table 2 summarizes studies investigating the antinociceptive
and anti-inflammatory effects of N. sativa and its main active
constituent TQ in different experimental models.
Potential antioxidant and anti-inflammatory
mechanisms according to in vitro studies
Numerous molecular targets are involved in the antioxidant and
anti-inflammatory activities of N. sativa and its active agents. As
reported by Singh et al., essential oil and oleoresins obtained
from black cumin seeds showed antioxidant effects with chelat-
ing activity on ferrous ions, a scavenging effect on 1,1-diphenyl-
2-picrylhydrazyl (DPPH) radical, and activity for the linseed oil
system. Meanwhile, such effects by essential oils were higher
than that observed by synthetic antioxidants such as buthylhy-
droxytoluene (BHT) and buthylhydroxyanisole (BHA) [19]. Both
the crude fixed oil of N. sativa and TQ dose-dependently attenu-
ated thromboxane B2 as well as leukotrienes (LT) B4 and C4 in rat
peritoneal leukocytes stimulated with calcium ionophore
A23187. Consequently, they can inhibit the cyclooxygenase
(COX) and 5-lipoxygenase (5-LPO) pathways of arachidonate me-
tabolism, respectively [66]. The inhibitory effect of fixed oil on
leukotriene generation and lipid peroxidation was greater than
that of thymoquinone. It seems that other ingredients, such as
unsaturated fatty acids, may also contribute to these protective
effects. Both compounds also inhibited nonenzymatic peroxida-
tion of brain phospholipid liposomes. In this pathway, the po-
tency of TQ was about ten times more than that of oil. Similarly,
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Mansour et al. reported that TQ potently inhibits the formation of
leukotrienes in human blood cells by inhibiting both 5-LPO and
LTC4 synthase activity [67].
Marsik et al. reported that quinolones from N. sativa seeds inhib-
ited COX-1 and 2. The most active ingredient against COX-1 was
thymol, while most inhibitory effects on COX-2 were observed
with THQ and TQ. Meanwhile, THQ was more specific for COX-2
than TQ [68]. Production of free radical nitric oxide (NO) by the
inducible nitric oxide synthase (iNOS) enzyme was dose- and
time-dependently inhibited by TQ in the supernatants of LPS-
stimulated macrophages [69].
In another study by Vaillancourt et al., TQ significantly abolished
LPS-induced proinflammatory cytokines such as interleukin-
1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), metallopro-
teinase-13 (MMP-13), COX-2, and prostaglandin E2 in an in vitro
model of rheumatoid arthritis [70].
There are enough investigations demonstrating that reactive
oxygen species (ROS), including NO, which subsequently causes
oxidative stress and mediators such as eicosanoids, proinflam-
matory cytokines, and lytic enzymes released by the inf lamma-
tory cells macrophages, microglia, and neutrophils, play an im-
portant role in the induction and maintenance of acute or chronic
conditions of pain [7177].
The inhibition of these targets is therefore exploited to attenuate
chronic conditions of pain, especially neuropathic pain [78, 79].
Another potential neuroprotective effect of thymoquinone might
be through the activation of PPAR-γ(peroxisome proliferator-ac-
tivated receptor γ) [80]. The activation of PPAR-γreduces estab-
lished neuropathic pain in addition to preventing its develop-
ment [81].
In addition, the phosphorylation of p38 mitogen-activated pro-
tein kinases (MAPK), extracellular-regulated kinases, and tran-
scriptional factor, and nuclear factor-kappa B (NF-κB) induced
by LPS were also blocked by TQ. The activation of MAPK and nu-
clear NF-κB has been demonstrated to contribute to chronic pain
states such as neuropathic pain [8284].
Potential antioxidant and anti-inflammatory
mechanisms according to in vivo studies
In line with the in vitro anti-inflammatory effects of N. sativa, in
vivo studies confirm such effects. Oral administration of TQ and
its metabolite dihydrothymoquinone (25, 50, and 100 mg/kg for
5 days to mice) showed superoxide anion scavenger activity in
different tissues [85]. An anti-inflammatory effect of TQ has been
reported in experimental allergic encephalomyelitis (EAE) in an
animal model for human multiple sclerosis by increasing the re-
duced glutathione (GSH) in the spinal cord of animals [86].
Oral administration of TQ (80 mg/kg) to diabetic rats for 45 days
reversed the decreased activities of catalase (CAT), glutathione
peroxidase (GPx), and glutathione-S-transferase (GST), and in-
creased antioxidants such as GSH and vitamins C and E, while it
attenuated levels of lipid peroxidation markers such as malon-
dialdehyde (MDA) in the kidney and liver tissues of diabetic rats
[87]. Similarly, in a study on rabbits, glutamate reductase, GPx,
Table 2 Selected studies showing the different doses and routes of administration of N. sativa seed components tested in experimental models of nociception
and inflammation.
Compound Dose Route Effect Animal Ref.
Volatile oil 0.66 and 1.55 mL/kg i. p. Decreased carrageenan-induced hind paws edema Rat [63]
Decreased cotton seed pellet granuloma
Thymoquinone 0.5, 1.0, 5 mg/kg
Fixed oil 50400 mg/kg oral Increased animal reaction time to hot plate Mice [52]
Increased animal reaction time in tail-pinch test
Inhibited acetic acid-induced writhing
Inhibited pain response in the first phase of formalin test
Thymoquinone 2.510 mg/kg oral Increased animal reaction time to hot plate Mice [52]
Increased animal reaction time in tail-pinch test
Inhibited acetic acid-induced writhing
16 mg/kg i. p. Inhibited pain response in both first and second phases of
formalin test
14 µg/mouse i. c.v
Aqueous extract 500 mg/kg oral Increased animal reaction time to hot plate Rats [54]
Decreased carrageenan-induced paw edema
Aqueous and methanolic
extracts
1.25 g/kg i. p. Increased animal reaction time to hot plate Mice [53]
Increased animal reaction time to Randall-Selitto
Polyphenols 200, 400, and 800 µL/kg oral Inhibited the earlyand late phases of formalin-induced pain Mice [64]
i.p.
200, 400, and 800 µL/kg Inhibited acetic acid-induced writhing
Inhibited carrageenan-induced paw edema
Essential oil 200, 400, and 800 µL/kg Inhibited croton oil-induced ear edema Rats [50]
Increased animal reaction time in light tail flick test
(only by essential oil)
Ethanolic extract 50 mg/kg i.p. Reduced acetic acid-induced writhing Mice [56]
Thymoquinone and para-
benzoquinones analogues
10 mg/kg i.p. Inhibited formalin-induced paw edema Mice [55]
Methanolic extract 1 g/kg oral Reduced kaolin-induced paw edema Rats [51]
Increased the reaction time on hot plate
Thymoquinone 2.5, 5 mg/kg i.p. Reduced neuropathic pain-induced allodynia and hyperalgesia Rats [109]
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and GST activity of the liver were induced by orally administered
TQ (10 and 20 mg/kg/day) for 8 weeks, which could explain the
effect of the black seeds in inhibiting the generation of bioactive
metabolites known to promote carcinogenesis and oxidative cell
damage. However, cytochrome enzymes (CYP1A2 and CYP3A4,
but not CYP2E1) were decreased by TQ treatment. Hence, it
seems that the potential drug interaction of TQ should be taken
into consideration [88]. Ulcerative colitis, a common clinical chal-
lenge, is a chronic inflammatory disorder in the gastrointestinal
tract with unknown etiology. In a gastric mucosal ischemia/re-
perfusion (I/R) injury model, thymoquinone (10 and 20mg/kg)
decreased gastric acid secretion, and acid output as well as the
gastric mucosal content/activity of lipid peroxide, the proton
pump, and myeloperoxidase (MPO) as a biomarker of inflamma-
tion along with the ulcer index. In contrast, GSH, total nitric ox-
ide, and superoxide dismutase (SOD) were decreased. Such ef-
fects were comparable to that of omeprazole as a reference drug
[89]. Moreover, thymoquinone showed protective effects on the
dextran sodium sulfate (DSS)-induced colitis with a significant
reduction in colonic MPO activity and MDA levels as well as an
increase in glutathione levels [90]. According to the work of Mah-
goub et al., acetic acid-induced colitis in rats was attenuated by
pretreatment with thymoquinone (10 mg/kg) for 3 days with a
comparable or even higher effect than sulfasalazine, a known
anti-colitis drug. In addition, the activity of MPO, platelet activat-
ing factor (PAF), and histamine, mediators of inflammation and
anaphylaxis, were decreased. In contrast, content of antioxidant
GSH was normalized [91].
However, in an earlier report by Juhás et al., TQ (0.05%) had no
protective effects against trinitobenzensulfonic acid (TNBS)-in-
duced colitis in mice [92]. In an ointment formulation, the black
seeds showed anti-inflammatory effects comparable to commer-
cial products [93].
The exposure of the brains of rats to lead revealed that TQ
(20 mg/kg, oral) for one month was able to ameliorate lead-in-
duced neuronal degeneration through inhibiting the microglial
reaction [94].
El-Mahmoudy and coworkers determined that the protective ef-
fects of TQ in streptozocine (STZ)-induced diabetic rats is mediat-
ed via inhibiting the phosphorylation of MAPK [69]. In an exper-
imental model of romatoid arthritis, the oral administration of
5 mg/kg/day thymoquinone significantly reduced the ser um lev-
els of proinflammatory cytokines, IL-1β, and TNF-αas well as
bone turnover markers such as alkaline phosphatase and tar-
trate-resistant acid phosphatase [70]. Similarly, thymoquinone
was found to inhibit IL-1β, 5-LPO, LTs B4 and C4, T helper 2 cyto-
kines (IL-4, IL-13, and IL-10), and eosinophils in the bronchoal-
veolar lavage fluid of ovalbumine-induced allergic asthma in
mice [95].
The aqueous extract of N. sativa (200 mg/kg, oral, for 5 days) and,
especially, the protein fraction of it possessed a potent protective
effect against tetrachloride carbon (CCL4)-induced hepatotoxic-
ity by a significant reduction of TNF-α, IL-1β, interferon gamma
(IFN-γ), and MDA levels, while it increased GSH content both in
serum and liver mice tissues. The ethanolic extract showed a less
protective effect in that study [96].
In one mouse model of experimentally induced morphine toler-
ance and dependence, brain oxidative stress and increased iNOS
expression were attenuated by coadministration with thymoqui-
none in mice. However, a morphine-induced progressive increase
in the brain glutamate level was not inhibited by this compound
[97]. Similarly, Gilhota et al. repor ted that thymoquinone (20 mg/
kg) significantly attenuated the immobilization-induced increase
in plasma NO levels of stressed mice [60]. Thymoquinone and
black cumin seed oil protected against the lipid peroxidation lev-
el after global cerebral ischemia-reperfusion injury in the hippo-
campus of rats [98]. In a recent work, N. sativa oil protection
against thioacetamide-induced liver injury was the result of scav-
enging the free radicals and protecting the liver cells against oxi-
dative damage [99].
In a stroke mode of rats, chloroform and petroleum ether ex-
tracts, and aqueous and hydroalcoholic extracts of N. sativa
(400 mg/kg, orally) for 7 days protected animals against focal ce-
rebral ischemia via a decrease in the concentration of thiobarbi-
turic acid reactive substance (TBARS) as well as via an increase in
the levels of GSH and antioxidant enzymes such as SOD and CAT
[100,101].
N. sativa and thymoquinone suppressed COX-2 and oxidative
stress markers by decreasing the levels of lipid peroxidation
MDA and increasing the level of SOD antioxidant enzyme in pan-
creatic tissue of STZ-induced diabetic rats [102].
Dariani and colleagues showed that the oral administration of
thymoquinone (10 mg/kg) attenuated seizure activity induced
by an intrahippocampal kainite model of temporal lobe epilepsy
in rats. Lipid peroxidation was attenuated by decreasing MDA, ni-
trite, and nitrate levels. Thymoquinone also lowered hippocam-
pal neuronal loss and mitigated astrogliosis [103].
In a model of vancomycin-induced nephrotoxicity in rats, thymo-
quinone (10 mg/kg, i. p.) for 8 days decreased kidney levels of
MDA; in contrast, it increased activities of SOD and GSHPx [104].
In addition, neuroprotective effects of thymoquinone have been
shown in the 6-hydroxydopamine-induced parkinsonism model
via decreasing the MDA and nit rite levels as well as increasing the
activity of SOD in the midbrain homogenate of rats [105].
Thymoquinone alleviated serum lipase, amylase, capase-1, and
MPO activity as well as proinflammatory cytokines (IL-1beta
and IL-18) in rats receiving ethanol and a high-fat diet. An opti-
mum protective effect was obtained with 100 mg/kg of thymo-
quinone [106].
Hepatic fibrosis was prevented by oral gavage of thymoquinone
(20 mg/kg or 40 mg/kg) through the regulation of phosphoryl-
ation of monophosphate-activated protein kinase (AMPK), liver
kinase B, and the inhibition of proinflammatory cytokines. The
expression of toll-like receptor 4 (TLR4) was also decreased by
thymoquinone [107]. Activation of this receptor has an important
role in inflammatory as well as neuropathic pain conditions.
After nerve injury, the activation of such a receptor induces mi-
croglia and astrocytes as well as the production of the proinflam-
matory cytokines in the spinal cord, leading to the development
and maintenance of inflammatory or neuropathic pain [108].
In a recent work, we examined the effects of thymoquinone on
the pain behavioral parameters in rats subjected to chronic con-
striction injury (CCI) of the left sciatic nerve as a neuropathic pain
model [109]. Anti-allodynia and anti-hyperalgesia effects ob-
served with thymoquinone (2.5 and 5 mg/kg, i. p.) were still evi-
dent after 2 weeks of treatment, which is in agreement with
those studies who suggest that the opioid system might have a
limited role in the antinociceptive effects of thymoquinone in
this model of neuropathic pain [52, 64]. We showed that antino-
ciceptive effects of thymoquinone might be attributed, in part, to
antioxidant activity, microglia activity inhibition, and a reduction
in the extent of apoptosis.
According to the Sethi et al. study, it is quite likely that many anti-
inflammatory activities assigned to N. sativa and its main constit-
Amin B, Hosseinzadeh H. Black Cumin (NigellaPlanta Med
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uent thymoquinone, including the effects on enzymes COX, iNOS,
and 5-LPO as well as proinflammatory cytokines such as TNF-α,
IL-1, and IL-6, may be mediated, in part, through the suppression
of NF-κB activation [110]. The expression of genes of many en-
zymes and cytokines are regulated by this transcription factor
[111]. The various molecular targets modulated by N. Sativa and
its major component thymoquinone are depicted in l
"Fig. 2 [69,
70,80, 95, 102,104, 105, 108].
Safety and Potential Toxicity
!
There are some studies suggesting that the therapeutic doses of
N. sativa and thymoquinone have low toxicity and a wide margin
of safety. Intraperitoneal administration of N. sativa (50 mg/kg)
for 5 days did not change the levels of enzymes and metabolites
in the liver and kidney of rats [23]. Zaoui et al. investigated the
acute and chronic toxicity of N. sativa fixed oil. Lethal dose 50%
(LD50) values obtained by single doses (acute study) were deter-
mined to be 28.8 mL/kg and 2.06 mL/kg after oral and intraperi-
toneal administration, respectively, in mice. In chronic toxicity,
rats were treated daily with an oral dose of 2 mL/kg for 12 weeks.
No changes were observed in the key hepatic enzymes levels, in-
cluding aspartate-aminotransferase, alanine-aminotranferase,
gamma-glutamyltransferase, and histopathological modifica-
tions in the heart, liver, kidneys, and pancreas after 12 weeks of
treatment. The serum cholesterol, triglyceride, and glucose levels
as well as the count of leukocytes and platelets decreased signifi-
cantly compared to the control animals. In contrast, hematocrit
and hemoglobin levels increased [112].
In another study, feeding Hibro broiler chicks with a diet contain-
ing 20 or 100 g/kg of N. sativa ground seeds for 7 weeks did not
adversely affect the animalsʼgrowth [113].
In an investigation using Sprague Dawley rats, the fixed oil of
black seed (4.0%) and the essential oil (0.30%) were safe, as sero-
logical factors such as liver and kidney functioning tests, serum
protein profile, cardiac enzymes as well as electrolyte balance re-
mained within normal values after 56 days. Similarly, indices of
red and white blood cells showed no significant variation. How-
ever, rats treated with the fixed oil moiety gained less weight
compared to the control, suggesting that black seeds could have
beneficial effects in obesity-related disorders [114].
In another study on mice, the LD50 of thymoquinone was
104.7 mg/kg and 870.9 mg/kg after oral and int raperitoneal ad-
ministrations, respectively, whereas the LD50 in rats was deter-
mined to be 57.5 mg/kg and 794.3 mg/kg after oral and intraper-
itoneal administration, respectively [115]. As reported by Man-
sour et al., thymoquinone was effective against CCl4-induced he-
patic damage only at a dose of 12.5 mg/kg, but not the higher
doses (25 and 50 mg/kg). It might be hypothesized that TQ at the
higher doses induces oxidative stress [116]. In a phase I clinical
study conducted on adult patients with advanced malignant can-
cers and treated with thymoquinone, oral doses of thymoqui-
none were tolerable for patients up to 2600 mg/day [117]. In a re-
cent study conducted by Tubesha and coworkeres on Sprague
Dawley rats, animals treated with 20 ml of thymoquinone-rich
fraction nanoemulsion (containing 44.5 mg/kg TQ) appeared
normal and there was no mortality or any signs of organ toxicity
during the 14-day experimental period [118]. Although, the oil of
N. sativa was marketed to treat disorders of skin such as acne and
eczema [119], two cases of allergic contact dermatitis were re-
ported after topical application of the oil in two persons who suf-
fered from maculopapular eczema [120,121].
Fig. 2 Different molecular targets of N. sativa and
thymoquinone in inflammatory diseases. CAT: cat-
alase; COX: cyclooxygenase; GPx: glutathione per-
oxidase; GSH: reduced glutathione; GST: gluta-
thione-S-transferase; IFN-γ: interferon gamma; IL:
interlukine; iNOS: inducible nitric oxide synthase; 5-
LPO: 5-lipooxygenase; p38MAPK: p38 mitogen-ac-
tivated protein kinases; MMP: matrix metallopro-
teinase; MPO: myeloperoxidase; NF-κB: nuclear fac-
tor-kappa B; PPAR-γ: peroxisome proliferator-acti-
vated receptor γ; SOD: superoxide dismutase; TLR-
4: toll-like receptor; TNF-α: tumor necrosis alpha
[69, 70, 80, 95, 102, 104, 105,108]. (Color figure
available online only.)
Amin B, Hosseinzadeh H. Black Cumin (NigellaPlanta Med
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Conclusion
!
N. sativa seeds contain a complex of more than 100 compounds,
some of which have not yet been studied or even identified. Un-
saturated fatty acids in fixed oil and essential oil components, es-
pecially thymoquinone, dithymoquinone, thymohydroquinone,
thymol, alkaloids, saponins, and vitamins as well as trace ele-
ments contribute to its health benefits associated with black cu-
min seeds. The original research articles published so far have
shown the antinociceptive and anti-inflammatory potential of
N. sativa seeds active ingredients, in particular, thymoquinone,
the main active constituent. Although the safety of N. sativa oil
and its active constituents has been investigated in some studies,
data on the bioavailability and other pharmacokinetic parame-
ters of this magic spice are still incomplete.
Furthermore, broad spectrum studies on specific cellular and
molecular mechanisms of action as well as controlled clinical tri-
als to prove its efficacy in humans are really needed to further as-
sess the application of N. sativa and/or thymoquinone as an anti-
nociceptive agent.
Conflict of Interest
!
The authors declare that there are no conflicts of interest.
References
1Datner AM. From medical herbalism to phytotherapy in dermatology:
back to the future. Dermatol Ther 2003; 16: 106113
2Mahfouz M, El-Dakhakhany M. The isolation of a crystalline active prin-
ciple from Nigella sativa L. seeds. J Pharm Sci 1960; 1: 119
3Latiff LA, Parhizkar S, Dollah MA, Hassan ST. Alternative supplement for
enhancement of reproductive health and metabolic profile among
perimenopausal women: a novel role of Nigella sativa. Iran J Basic
Med Sci 2014; 17: 980985
4Kaatabi H, Bamosa AO, Badar A, Al-Elq A, Abou-Hozaifa B, Lebda F, Al-
Khadra A, Al-Almaie S. Nigella sativa improves glycemic control and
ameliorates oxidative stress in patients with type 2 diabetes mellitus:
placebo controlled participant blinded clinical trial. PLoS One 2015;
10: e0113486
5Khader M, Eckl PM. Thymoquinone: an emerging natural drug with a
wide range of medical applications. Iran J Basic Med Sci 2014; 17:
950957
6Ramadan MF. Nutritional value, functional properties and nutraceuti-
cal applications of black cumin (Nigella sativa L.): an overview. Int
J Food Sci Technol 2007; 42: 12081218
7Al-Jassir MS. Chemical composition and microflora of black cumin (Ni-
gella sativa L.) seeds growing in Saudi Arabia. Food Chem 1992; 45:
239242
8Kamal A, Arif JM, Ahmad IZ. Potential of Nigella sativa L. seed dur ing dif-
ferent phases of germination on inhibition of bacterial growth.
E3 J Biotech Pharm Res 2010; 1: 913
9Cheikh-Rouhou S, Besbes S, Hentati B, Blecker C, Deroanne C, Attia H. Ni-
gella sative L., chemical composition and physicochemical charachter-
istics of lipid fraction. Food Chem 2007; 101: 673681
10 Hadad GM, Salam RA, Soliman RM, Mesbah MK. High-performance liq-
uid chromatography quantification of principal antioxidants in black
seed (Nigella sativa L.) phytopharmaceuticals. J AOAC Int 2012; 95:
10431047
11 Al-Saleh IA, Billedo G, El-Doush II. Levels of selenium, dl-α-tocopherol,
dl-γ-tocopherol, all-trans-retinol, thymoquinone and thymol in differ-
ent brands of Nigella sativa seeds. J Food Compost Anal 2006; 19: 167
175
12 Muhammad TS. Characterization of black cumin seed oil and exploring
its role as a functional food. Faisalabad: University of Agriculture; 2009
13 Gad AM, El-Dakhakhany M, Hassan MM. Studies on the chemical con-
stitution of Egyptian Nigella sativa L. oil. Planta Med 1963; 11: 134
138
14 Atta UR, Malik S, Hasan SS, Choudhary MI, Chao-Zhou N, Clardy J. Nigel-
lidine, a new indazole alkaloid from seeds of Nigella sativa. Tetrahe-
dron Lett 1995; 36: 19931996
15 Sultan MT, Butt MS, Anjum FM, Jamil A, Akhtar S, Nasir M. Nutritional
profile of indigenous cultivar of black cumin seeds and antioxidant po-
tential of its fixed and essential oil. Pak J Bot 2009; 41: 13211330
16 El-Tahir Kamal EH, Bakeet DM. The Black seed Nigella sativa Linnaeus
a mine for multi cures: a plea for urgent clinical evaluation of its vola-
tile oil. J T U Med Sci 2006; 1: 119
17 Ansari AA, Hassan S, Kenne L, Wehler T. Structural studies on a saponin
isolated from Nigella sativa. Phytochemistry 1988; 27: 39773979
18 Burits M, Bucar F. Antioxidant activity of Nigella sativa essential oil.
Phytother Res 2000; 14: 323328
19 Singh S, Das SS, Singh G, Schuff C, de Lampasona MP, Catalan CA. Compo-
sition, in vitro antioxidant and antimicrobial activities of essential oil
and oleoresins obtained from black cumin seeds (Nigella sativa L.). Bi-
omed Res Int 2014; 2014: 10
20 Ghosheh OA, Houdi AA, Crooks PA. High performance liquid chromato-
graphic analysis of the pharmacologically active quinones and related
compounds in the oil of the black seed (Nigella sativa L.). J Pharm Bi-
omed Anal 1999; 19: 757762
21 Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for
inflammatory disorders and cancer. Biochem Pharmacol 2012; 83:
443451
22 Heiss AG, Stika HP, De Zorzi N, Jursa M. Nigella in the mirror of time a
brief attempt to draw a genusʼethnohistorical portrait. Offa 2012; 69/
70: 147169
23 Junemann M, Luetjohann S. Three great healing herbs: tea tree, St. Johns
wort, and black cumin. Twin Lakes, WI: L otus Light Publications; 1998:
91116
24 Nergiz C, ÖtleşS. Chemical composition of Nigella sativa L. seeds. Food
Chem 1993; 48: 259261
25 Ziaei T, Moharreri N, Hosseinzadeh H. Review of pharmacological and
toxicological effects of Nigella sativa and its active constituents. J Med
Plants 2012; 11: 1642
26 Ali BH, Blunden G. Pharmacological and toxicological properties of Ni-
gella sativa. Phytother Res 2003; 17: 299305
27 El Daly ES. Protective effect of cysteine and vitamin E, Crocus sativus
and Nigella sativa extracts on cisplatin-induced toxicity in rats. J Pharm
Belg 1998; 53: 8793
28 Cikman O, Ozkan A, Aras AB, Soylemez O, Alkis H, Taysi S, Karaayvaz M.
Radioprotective effects of Nigella Sativa oil against oxidative stress in
liver tissue of rats exposed to total head irradiation. J Invest Surg
2014; 5: 262266
29 Burits M, Bucar F. Antioxidant activity of Nigella sativa essential oil.
Phytother Res 2000; 14: 323328
30 Mousavi S, Tayarani-Najaran Z, Asghari M, Sadeghnia H. Protective ef-
fect of Nigella sat iva extract and thymoquinone on serum/glucose dep-
rivation-induced PC12 cells death. Cell Mol Neurobiol 2010; 30: 591
598
31 Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. The protec-
tive effect of thymoquinone, an anti-oxidant and anti-inflammatory
agent, against renal injury: a review. Saudi J Kidney Dis Transpl 2009;
20: 741752
32 Awad E, Austin D, Lyndon AR. Effect of black cumin seed oil (Nigella sat-
iva) and nettle extract (Quercetin) on enhancement of immunity in
rainbow trout, Oncorhynchus mykiss (Walbaum). Aquaculture 2013;
388391: 193197
33 Assayed ME. Radioprotective effects of black seed (Nigella sativa)oil
against hemopoietic damage and immunosuppression in gamma-irra-
diated rats. Immunopharmacol Immunotoxicol 2010; 32: 284296
34 Abdel-Sater KA. Gastroprotective effects of Nigella Sativa oil on the for-
mation of stress gastritis in hypothyroidal rats. Int J Physiol Pathophy-
siol Pharmacol 2009; 1: 143149
35 Mahmoud MR, El-Abhar HS, Saleh S. The effect of Nigella sativa oil
against the liver damage induced by Schistosoma mansoni infection
in mice. J Ethnopharmacol 2002; 79: 111
36 Hosseinzadeh H, Eskandari M, Ziaee T. Antitussive effect of thymoqui-
none, a constituent of Nigella Sativa seeds, in guinea pigs. Pharmacolo-
gyonline 2008; 2: 480484
37 Ibrahim RM, Hamdan NS, Mahmud R, Imam MU, Saini SM, Rashid SN,
Abd Ghafar SA, Latiff LA, Ismail M. A randomised controlled trial on hy-
polipidemic effects of Nigella Sativa seeds powder in menopausal
women. J Transl Med 2014; 12: 82
Amin B, Hosseinzadeh H. Black Cumin (NigellaPlanta Med
Reviews
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
38 Ebru U, Burak U, Yusuf S, Reyhan B, Arif K, Faruk TH, Emin M, Aydin K,
Atilla II, Semsettin S, Kemal E. Cardioprotective effects of Nigella sativa
oil on cyclosporine A-induced cardiotoxicity in rats. Basic Clin Pharma-
col Toxicol 2008; 103: 574580
39 Nagi MN, Mansour MA. Protective effect of thymoquinone against
doxorubicin-induced cardiotoxicity in rats: a possible mechanism of
protection. Pharmacol Res 2000; 41: 283289
40 Hosseinzadeh H, Tafaghodi M, Mosavi MJ, Taghiabadi E. Effect of aque-
ous and ethanolic extracts of Nigella sativa seeds on milk production
in rats. J Acupunct Meridian Stud 2013; 6: 1823
41 Meddah B, Ducroc R, El Abbes Faouzi M, Eto B, Mahraoui L, Benhaddou-
Andaloussi A, Martineau LC, Cherrah Y, Haddad PS. Nigella sativa inhib-
its intestinal glucose absorption and improves glucose tolerance in
rats. J Ethnopharmacol 2009; 121: 419424
42 Zaoui A, Cherrah Y, Lacaille-Dubois MA, Settaf A, Amarouch H, Hassar M.
Diuretic and hypotensive effects of Nigella sativa in the spontaneously
hypertensive rat. Therapie 2000; 55: 379382
43 Hanafy MS, Hatem ME. Studies on the antimicrobial activity of Nigella
sativa seed (black cumin). J Ethnopharmacol 1991; 34: 275278
44 Dey D, Ray R, Hazra B. Antitubercular and antibacterial activity of qui-
nonoid natural products against multi-drug resistant clinical isolates.
Phytother Res 2014; 28: 10141021
45 Hosseinzadeh H, Parvardeh S, Nassiri-Asl M, Mansouri MT. Intracerebro-
ventricular administration of thymoquinone, the major constituent of
Nigella sativa seeds, suppresses epileptic seizures in rats. Med Sci Mon-
it 2005; 11: BR106BR110
46 Damião PD, Franklin FFN, Camila CMPS, Rubens BB, Ygor WV, Marciana
PU, Timothy JB, Reinaldo ND. Anticonvulsant activity of thymoquinone
and its structural analogues. Rev Bras Farmacogn 2011; 21: 427433
47 Perveen T, Haider S, Zuberi NA, Saleem S, Sadaf S, Batool Z. Increased 5-
HT levels following repeated administration of Nigella sativa L. (black
seed) oil produce antidepressant effects in rats. Sci Pharm 2014; 82:
161170
48 Kolahdooz M, Nasri S, Modarres SZ, Kianbakht S, Huseini HF. Effects of
Nigella sativa L. seed oil on abnormal semen quality in infertile men:
a randomized, double-blind, placebo-controlled clinical trial. Phyto-
medicine 2014; 21: 901905
49 Hosseini M, Mohammadpour T, Karami R, Rajaei Z, Sadeghnia HR,
Soukhtanloo M. Effects of the hydro-alcoholic extract of Nigella sativa
on scopolamine-induced spatial memory impairment in rats and its
possible mechanism. Chin J Integr Med 2015; 21: 438444
50 Ghannadi A, Hajhashemi V, Jafarabadi H. An investigation of the analge-
sic and anti-inflammatory effects of Nigella sativa seed polyphenols.
J Med Food 2005; 8: 488493
51 Islam MH, Ahmad IZ, Salman MT. In vivo evaluation of anti-inflamma-
tory and analgesic activies of Nigella sativa seed during germination.
Int J Pharm Pharm Sci 2013; 5: 451454
52 Abdel-Fattah AM, Matsumoto K, Watanabe H. Antinociceptive effects of
Nigella sativa oil and its major component, thymoquinone, in mice. Eur
J Pharmacol 2000; 400: 8997
53 Al-Naggar TB, Gomez-Serranillos MP, Carretero ME, Villar AM. Neuro-
pharmacological activity of Nigella sativa L. extracts. J Ethnopharmacol
2003; 88: 6368
54 Al-Ghamdi MS. The anti-inflammatory, analgesic and antipyretic activ-
ity of Nigella sativa. J Ethnopharmacol 2001; 76: 4548
55 De Sousa DP, Nóbrega FF, Santos CC, Benedito RB, Vieira YW, Uliana MP,
Brocksom TJ, de Almeida RN. Antinociceptive activity of thymoquinone
and its structural analogues: a structure-activity relationship study.
Trop J Pharm Res 2012; 11: 605610
56 Bashir MU, Qureshi HJ. Analgesic effect of Nigella sativa seeds extract on
experimentally induced pain in albino mice. J Coll Physicians Surg Pak
2010; 20: 464467
57 Dickenson AH, Chapman V, Green GM. The pharmacology of excitatory
and inhibitory amino acid-mediated events in the transmission and
modulation of pain in the spinal cord. Gen Pharmacol 1997; 28: 633
638
58 Enna SJ, McCarson KE. The role of GABA in the mediation and percep-
tion of pain. Adv Pharmacol 2006; 54: 127
59 El-Naggar T, Gómez-Serranillos MP, Palomino OM, Arce C, Carretero ME.
Nigella sativa L. seed extract modulates the neurotransmitter amino
acids release in cultured neurons in vitro. J Biomed Biotechnol 2010;
2010: 398312
60 Gilhotra N, Dhingra D. Thymoquinone produced antianxiety-like ef-
fects in mice through modulation of GABA and NO levels. Pharmacol
Rep 2011; 63: 660669
61 Marks DM, Shah MJ, Patkar AA, Masand PS, Park GY, Pae CU. Serotonin-
norepinephrine reuptake inhibitors for pain control: premise and
promise. Curr Neuropharmacol 2009; 7: 331336
62 Lee YC, Chen PP. A review of SSRIs and SNRIs in neuropathic pain. Ex-
pert Opin Pharmacother 2010; 11: 28132825
63 Mutabagani A, El-Mahdy SAM. A study of the anti-inflammatory activ-
ity of Nigella sativa L. and thymoquinone in rats. Saudi Pharm J 1997; 5:
110113
64 Hajhashemi V, Ghannadi A, Jafarabadi H. Black cumin seed essential oil,
as a potent analgesic and antiinflammatory drug. Phytother Res 2004;
18: 195199
65 Kamal A, Arif JM, Ahmad IZ. Potential of Nigella sativa L. seed dur ing dif-
ferent phases of germination on inhibition of bacterial growth.
J Biotech Pharm Res 2010; 1: 913
66 Houghton PJ, Zarka R, de las Heras B, Hoult JR. Fixed oil of Nigella sativa
and derived thymoquinone inhibit eicosanoid generation in leukocytes
and membrane lipid peroxidation. Planta Med 1995; 61: 3336
67 Mansour M, Tornhamre S. Inhibition of 5-lipoxygenase and leukotriene
C4 synthase in human blood cells by thymoquinone. J Enzyme Inhib
Med Chem 2004; 19: 431436
68 Marsik P, Kokoska L, Landa P, Nepovim A, Soudek P, Vanek T. In vitro in-
hibitory effects of thymol and quinones of Nigella sativa seeds on cy-
clooxygenase-1-and-2-catalyzed prostaglandin E2 biosyntheses. Plan-
ta Med 2005; 71: 739742
69 El-Mahmoudy A, Matsuyama H, Borgan MA, Shimizu Y, El-Sayed MG,
Minamoto N, Takewaki T. Thymoquinone suppresses expression of in-
ducible nitric oxide synthase in rat macrophages. Int Immunopharma-
col 2002; 2: 16031611
70 Vaillancourt F, Silva P, Shi Q, Fahmi H, Fernandes JC, Benderdour M. Elu-
cidation of molecular mechanisms underlying the protective effects of
thymoquinone against rheumatoid arthritis. J Cell Biochem 2011; 112:
107117
71 Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neu-
ropathic pain. Brain Res Rev 2006; 51: 240264
72 Sliva J, Prochazkova M, Dolezal T. The role of cyclooxygenase in pain
processing in CNS. Cesk Fysiol 2004; 53: 176180
73 Chung JM. The role of reactive oxygen species (ROS) in persistent pain.
Mol Interv 2004; 4: 248250
74 Berger JV, Deumens R, Goursaud S, Schafer S, Lavandʼhomme P, Joosten
EA, Hermans E. Enhanced neuroinflammation and pain hypersensitiv-
ity after peripheral ner ve injury in rats expressing mutated superoxide
dismutase 1. J Neuroinflammation 2011; 8: 33
75 Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodege-
nerative diseases. Immunology 2010; 129: 154169
76 Noguchi K, Okubo M. Leukotrienes in nociceptive pathway and neuro-
pathic/inflammatory pain. Biol Pharm Bull 2011; 34: 11631169
77 Vallejo R, Tilley DM, Vogel L, Benyamin R. The role of glia and the im-
mune system in the development and maintenance of neuropathic
pain. Pain Pract 2010; 10: 167184
78 Zhu X, Li Q, Chang R, Yang D, Song Z, Guo Q, Huang C. Curcumin alleviates
neuropathic pain by inhibiting p 300/CBP histone acetyltransferase ac-
tivity-regulated expression of BDNF and cox-2 in a rat model. PLoS One
2014; 9: e91303
79 Ko YK, Youn AM, Hong BH, Kim YH, Shin YS, Kang PS, Yoon KJ, Lee WH.
Antinociceptive effect of phenyl N-tert-butylnitrone, a free radical
scavenger, on the rat formalin test. Korean J Anesthesiol 2012; 62:
558564
80 Woo CC, Loo SY, Gee V, Yap CW, Sethi G, Kumar AP, Tan KH. Anticancer
activity of thymoquinone in breast cancer cells: possible involvement
of PPAR-γpathway. Biochem Pharmacol 2011; 82: 464475
81 Griggs RB, Donahue RR, Morgenweck J, Grace PM, Sutton A, Watkins LR,
Taylor BK. Pioglitazone rapidly reduces neuropathic pain through as-
trocyte and nongenomic PPARγmechanisms. Pain 2015; 156: 469482
82 Jeon Y, Kim CE, Jung D, Kwak K, Park S, Lim D, Kim S, Baek W. Curcumin
could prevent the development of chronic neuropathic pain in rats
with peripheral nerve injury. Curr Ther Res Clin Exp 2013; 74: 14
83 Obata K, Noguchi K. MAPK activation in nociceptive neurons and pain
hypersensitivity. Life Sci 2004; 74: 26432653
84 Lee MK, Han SR, Park MK, Kim MJ, Bae YC, Kim SK, Park JS, Ahn DK. Behav-
ioral evidence for the differential regulation of p-p38 MAPK and p-NF-
kappaB in rats with trigeminal neuropathic pain. Mol Pain 2011; 7: 57
85 Mansour MA, Nagi MN, El-Khatib AS, Al-Bekairi AM. Effects of thymo-
quinone on antioxidant enzyme activities, lipid peroxidation and DT-
diaphorase in different tissues of mice: a possible mechanism of action.
Cell Biochem Funct 2002; 20: 143151
Amin B, Hosseinzadeh H. Black Cumin (NigellaPlanta Med
Reviews
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
86 Mohamed A, Shoker A, Bendjelloul F, Mare A, Alzrigh M, Benghuzzi H,
Desin T. Improvement of experimental allergic encephalomyelitis
(EAE) by thymoquinone; an oxidative stress inhibitor. Biomed Sci Ins-
trum 2003; 39: 440445
87 Sankaranarayanan C, Pari L. Thymoquinone ameliorates chemical in-
duced oxidative stress and beta-cell damage in experimental hyper-
glycemic rats. Chem Biol Interact 2011; 190: 148154
88 Elbarbry F, Ragheb A, Marfleet T, Shoker A. Modulation of hepatic drug
metabolizing enzymes by dietary doses of thymoquinone in female
New Zealand White rabbits. Phytother Res 2012; 26: 17261730
89 Magdy MA, Hanan el-A, Nabila el-M. Thymoquinone: Novel gastropro-
tective mechanisms. Eur J Pharmacol 2012; 697: 126131
90 Lei X, Liu M, Yang Z, Ji M, Guo X, Dong W. Thymoquinone prevents and
ameliorates dextran sulfate sodium-induced colitis in mice. Dig Dis
Sci 2012; 57: 22962303
91 Mahgoub AA. Thymoquinone protects against experimental colitis in
rats. Toxicol Lett 2003; 143: 133143
92 Juhas S, Cikos S, Czikkova S, Vesela J, Ilʼkova G, Hajek T, Domaracka K,
Domaracky M, Bujnakova D, Rehak P, Koppel J. Effects of borneol and
thymoquinone on TNBS-induced colitis in mice. Folia Biol (Praha)
2008; 54: 17
93 Zedlitz S, Kaufmann R, Boehncke WH. Allergic contact dermatitis from
black cumin (Nigella sativa) oil-containing ointment. Contact Derma-
titis 2002; 46: 188
94 Radad K, Hassanein K, Al-Shraim M, Moldzio R, Rausch WD. Thymoqui-
none ameliorates lead-induced brain damage in Sprague Dawley rats.
Exp Toxicol Pathol 2014; 66: 1317
95 El Gazzar M, El Mezayen R, Marecki JC, Nicolls MR, Canastar A, Dreskin
SC. Anti-inflammatory effect of thymoquinone in a mouse model of
allergic lung inflammation. Int Immunopharmacol 2006; 6: 1135
1142
96 Michel CG, El-Sayed NS, Moustafa SF, Ezzat SM, Nesseem DI, El-Alfy TS.
Phytochemical and biological investigation of the extracts of Nigella
sativa L. seed waste. Drug Test Anal 2011; 3: 245254
97 Abdel-Zaher AO, Mostafa MG, Farghly HM, Hamdy MM, Omran GA, Al-
Shaibani NK. Inhibition of brain oxidative stress and inducible nitric
oxide synthase expression by thymoquinone attenuates the develop-
ment of morphine tolerance and dependence in mice. Eur J Pharmacol
2013; 702: 6270
98 Hosseinzadeh H, Parvardeh S, Asl MN, Sadeghnia HR, Ziaee T. Effect of
thymoquinone and Nigella sativa seeds oil on lipid peroxidation level
during global cerebral ischemia-reperfusion injury in rat hippocam-
pus. Phytomedicine 2007; 14: 621627
99 Nehar S, Kumari M. Ameliorating effect of Nigella sativa oil in thioace-
tamide-induced liver cirrhosis in albino rats. Ind J Pharm Edu Res
2013; 47: 135139
100 Akhtar M, Maikiyo AM, Najmi AK, Khanam R, Mujeeb M, Aqil M. Neuro-
protective effects of chloroform and petroleum ether extracts of Ni-
gella sativa seeds in stroke model of rat. J Pharm Bioallied Sci 2013;
5: 119125
101 Akhtar M, Maikiyo AM, Khanam R, Mujeeb M, Aqil M, Najmi AK. Ameli-
orating effects of two extracts of Nigella sativa in middle cerebral ar-
tery occluded rat. J Pharm Bioallied Sci 2012; 4: 7075
102 Al Wafai RJ. Nigella sativa and thymoquinone suppress cyclooxygen-
ase-2 and oxidative stress in pancreatic tissue of streptozotocin-in-
duced diabetic rats. Pancreas 2013; 42: 841849
103 Dariani S, Baluchnejadmojarad T, Roghani M. Thymoquinone attenu-
ates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxi-
dative stress in a model of temporal lobe epilepsy. J Mol Neurosci
2013; 3: 679686
104 Basarslan F, Yilmaz N, Ates S, Ozgur T, Tutanc M, Motor VK, Arica V, Yil-
maz C, Inci M, Buyukbas S. Protective effects of thymoquinone on van-
comycin-induced nephrotoxicity in rats. Hum Exp Toxicol 2012; 31:
726733
105 Sedaghat R, Roghani M, Khalili M. Neuroprotective effect of thymoqui-
none, the Nigella sativa bioactive compound, in 6-hydroxydopamine-
induced hemi-parkinsonian rat model. Iran J Pharm Res 2014; 13:
227234
106 Suguna P, Geetha A, Aruna R, Siva GV. Effect of thymoquinone on etha-
nol and high fat diet induced chronic pancreatitis-a dose response
study in rats. Indian J Exp Biol 2013; 51: 292302
107 Bai T, Yang Y, Wu YL, Jiang S, Lee JJ, Lian LH, Nan JX. Thymoquinone al-
leviates thioacetamide-induced hepatic fibrosis and inflammation by
activating LKB1-AMPK signaling pathway in mice. Int Immunophar-
macol 2014; 19: 351357
108 Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, Klinman D, Oppenheim JJ,
Howard OM. Painful pathways induced by TLR stimulation of dorsal
root ganglion neurons. J Immunol 2011; 186: 64176426
109 Amin B, Taheri Heravi MM, Hosseinzadeh H. Effects of intraperitoneal
thymoquinone on chronic neuropathic pain in rats. Planta Med, ad-
vance online publication 1 October 2014; DOI: 10.1055/s-0034
1383062
110 Sethi G, Ahn KS, Aggarwal BB. Targeting nuclear factor-kappa B activa-
tion pathway by thymoquinone: role in suppression of antiapoptotic
gene products and enhancement of apoptosis. Mol Cancer Res 2008;
6: 10591070
111 Ahn KS, Aggarwal BB. Transcription factor NF-kappaB: a sensor for
smoke and stress signals. Ann N Y Acad Sci 2005; 1056: 218233
112 Zaoui A, Cherrah Y, Mahassini N, Alaoui K, Amarouch H, Hassar M.
Acute and chronic toxicity of Nigella sativa fixed oil. Phytomedicine
2002; 9: 6974
113 Al-Homidan A, Al-Qarawi AA, Al-Waily SA, Adam SE. Response of
broiler chicks to dietary Rhazya stricta and Nigella sativa. Br Poult Sci
2002; 43: 291296
114 Tauseef Sultan M, Butt MS, Anjum FM. Safety assessment of black cu-
min fixed and essential oil in normal Sprague Dawley rats: serological
and hematological indices. Food Chem Toxicol 2009; 47: 27682775
115 Al-Ali A, Alkhawajah AA, Randhawa MA, Shaikh NA. Oral and intraper-
itoneal LD50 of thymoquinone, an active principle of Nigella sativa,in
mice and rats. J Ayub Med Coll Abbottabad 2008; 20: 2527
116 Mansour MA, Ginawi OT, El-Hadiyah T, El-Khatib AS, Al-Shabanah OA,
Al-Sawaf HA. Effects of volatile oil constituents of Nigella sativa on
carbon tetrachloride-induced hepatotoxicity in mice: evidence for
antioxidant effects of thymoquinone. Res Commun Mol Pathol Phar-
macol 2001; 110: 239251
117 Al-Amri AM, Bamosa AO. Phase I safety and clinical activity study of
thymoquinone in patients with advanced refractory malignant dis-
ease. Shiraz E Med J 2009; 10: 107111
118 Tubesha Z, Imam MU, Mahmud R, Ismail M. Study on the potential tox-
icity of a thymoquinone-rich fraction nanoemulsion in Sprague Daw-
ley rats. Molecules 2013; 18: 74607472
119 Yousefi M, Barikbin B, Kamalinejad M, Manouchehrian M, Hejazi S.
Comparison of therapeutic effect of topical Nigella with betametha-
sone and eucerin in hand eczema. J Eur Acad Dermatol Venereol
2013; 27: 14981504
120 Steinmann A, Schatzle M, Agathos M, Breit R. Allergic contact dermati-
tis from black cumin ( Nigella sativa) oil after topical use. Contact Der-
matitis 1997; 36: 268269
121 Nosbaum A, Ben Said B, Halpern SJ, Nicolas JF, Berard F. Systemic aller-
gic contact dermatitis to black cumin essential oil expressing as gen-
eralized erythema multiforme. Eur J Dermatol 2011; 21: 447448
Amin B, Hosseinzadeh H. Black Cumin (NigellaPlanta Med
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... CQ and HCQ have a temporary inhibitory effect on the entry of SARS-CoV-2 through changing the pH of the perfusion fluid. The issue can be reversed when either of the drugs is removed, while TQ increases endosomal pH, preventing SARS-CoV-2 entry into the cell, together with simultaneously attacking the virus due to the two single oxygens in the TQ molecule, thereby acting as both a shield and sword [81]. Moreover, the cationic amphiphilic nature of CQ and HCQ [82] results in their immobilization in the hydrophilic environment through the body, with the inability to reach the target organs. ...
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In today’s world, the outbreak of the coronavirus disease 2019 (COVID-19) has spread throughout the world, causing severe acute respiratory syndrome (SARS) and several associated complications in various organs (heart, liver, kidney, and gastrointestinal tract), as well as significant multiple organ dysfunction, shock, and even death. In order to overcome the serious complications associated with this pandemic virus and to prevent SARS-CoV-2 entry into the host cell, it is necessary to repurpose currently available drugs with a broad medicinal application as soon as they become available. There are several therapeutics under investigation for improving the overall prognosis of COVID-19 patients, but none of them has demonstrated clinical efficacy to date, which is disappointing. It is in this pattern that Nigella sativa seeds manifest their extensive therapeutic effects, which have been reported to be particularly effective in the treatment of skin diseases, jaundice, and gastrointestinal problems. One important component of these seeds is thymoquinone (TQ), which has a wide range of beneficial properties, including antioxidant and anti-inflammatory properties, as well as antibacterial and parasitic properties, in addition to anticarcinogenic, antiallergic, and antiviral properties. This comprehensive review discussed the possibility of an emerging natural drug with a wide range of medical applications; the use of TQ to overcome the complications of COVID-19 infection; and the challenges that are impeding the commercialization of this promising phytochemical compound. TQ is recommended as a highly effective weapon in the fight against the novel coronavirus because of its dual antiviral action, in addition to its capacity to lessen the possibility of SARS-CoV-2 penetration into cells. However, future clinical trials are required to confirm the role of TQ in overcoming the complications of COVID-19 infection.
... However, Also, vitamins (1-4%), proteins (25%), carbohydrates (33%), alkaloids (0.01%), fixed oil (22-38%), minerals (3.7-7%), essential oil (0.40-1.5%), and saponins (0.013%) are included in its composition. Different components in its content are responsible for the different effects of NS [34]. It can be revealed which compound is for which target with further studies. ...
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