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Dermatological effects of Nigella sativa
Salih H.M. Aljabre, Omar M. Alakloby, Mohammad A. Randhawa
PII: S2352-2410(15)00028-6
DOI: http://dx.doi.org/10.1016/j.jdds.2015.04.002
Reference: JDDS 33
To appear in: Journal of Dermatology & Dermatologic Surgery
Received Date: 16 April 2015
Accepted Date: 25 April 2015
Please cite this article as: S.H.M. Aljabre, O.M. Alakloby, M.A. Randhawa, Dermatological effects of Nigella sativa,
Journal of Dermatology & Dermatologic Surgery (2015), doi: http://dx.doi.org/10.1016/j.jdds.2015.04.002
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Title:
Dermatological effects of Nigella sativa
Authors:
1. Salih H. M. Aljabre, MBBS, MSC, PhD
Department of Dermatology, College of Medicine, King Fahd hospital of the university,
University of Dammam, Dammam, Saudi Arabia
2. Omar M. Alakloby, MBBS, KFUF
Department of Dermatology, College of Medicine, King Fahd hospital of the university,
University of Dammam, Dammam, Saudi Arabia
3. Mohammad A Randhawa, MBBS, M Phil, PhD
Department of Pharmacology, College of Medicine, Northern Border University, P.O. Box 1321,
Arar 91431, Saudi Arabia
Key words: Nigella. Sativa seed, black seed oil, active components, dermatological effects,
Nigella sativa and the skin
Running title:
Dermatological effects of Nigella sativa
Correspondence:
1. Salih H Aljabre, MBBS, MSC, PhD
Department of Dermatology, King Fahd hospital of the university, university of Dammam, P.O.
Box 2208, Alkhobar 31952, Saudi Arabia
Saljabre@yahoo.com ,, sjabre@uod.edu.sa
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Dermatological effects of Nigella sativa
Abstract
Nigella sativa seed, commonly known as black seed, has been employed as a natural remedy for many ailments
for centuries in many cultures. It contains many active components including thymoquinone,
thymohydroquinone, dithymoquinone, thymol, carvacrol, nigellimine, nigellicine, nigellidine and alphahederin. It
was reported to possess numerous pharmacological effects related to several organs of the body. In this article,
the literature pertaining to dermatological effects of Nagilla sativa is reviewed. To the best of our knowledge this
is the first review in this subject and we expect it stimulates further studies on the dermatological effects and
application of nigella sativa.
Introduction
Nigella sativa (N. sativa) belongs to the botanical family of Ranunculaceae and commonly grows in the Eastern
Europe, Middle East, and Western Asia. It is a small shrub with tapering green leaves and rosaceous white and
purplish flowers. Its ripe fruit contains tiny seeds, dark black in colour, known as “Habba Al-Sauda” or “Habba Al-
Barakah” in Arabic and black seed in English. The seed and oil of N. sativa were frequently used in ancient
remedies (Unani, Ayurveda, Chinese and Arabic) in Asian countries and in the middle east. Several uses of the N.
sativa seed had been mentioned by the Ibne-Sina (980-1037) in his famous book Al-Qanoon fi el-Tibb (1,2).
Numerous active components have been isolated from N. sativa seed and its oil including thymoquinone,
thymohydroquinone, dithymoquinone, thymol, carvacrol, nigellimine-N-oxide, nigellicine, nigellidine and alpha-
hederin. The pharmacological properties of N. sativa and its ingredients had been investigated by in vitro and in
vivo studies conducted on human and laboratory animals. These studies showed that N. sativa and its ingredients
have wide range of pharmacological effects; immune-stimulatory, anti-inflammatory, hypoglycemic,
antihypertensive, antiasthmatic, antimicrobial, antiparasitic, antioxidant and anticancer effects (reviewed in 3 – 8).
Acute and chronic toxicity studies on laboratory animals have reported that N. sativa seed, its oil and
thymoquinone, the most abundant and widely studied active principle, are safe, particularly when given orally (9-
11). The objective of this article is to review the reported dermatological effects of N. sativa . An online and
PubMed search of published articles related to the dermatological effects of N. sativa seed, its oil and active
ingredients was conducted. Only articles substantiated by appropriate scientific methodology were reviewed and
included. The following are categories of the studies: antimicrobial, antiviral, antifungal, antiparasitic, wound
healing, psoriasis, acne vulgaris, vitiligo, skin cancer, percutaneous absorption, cosmetic application and cutaneous
side effects.
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Antibacterial
Topozada et al 1965 (12) were first to report the antibacterial effect of the phenolic fraction of N. sativa oil. El-
Fatatry (13) isolated thymohydroquinone from the volatile oil of N. sativa, which was found to have high activity
against gram-positive microorganisms, including Staph aureus. Diethyl-ether extract of N. sativa was reported to
possess concentration dependent inhibitory effect on gram-positive bacteria (represented by Staphylococcus
aureus) and gram-negative bacteria (represented by Pseudomonas aerogenosa and Escherichia coli) (14) . It also
showed synergistic effect with streptomycin and gentamycin and additive effect with spectinomycin,
erythromycin, tobramycin, doxycycline, chloramphenicol, nalidixic acid, ampicillin, lincomycin and co-trimoxazole
and successfully eradicated a non-fatal subcutaneous staphylococcal infection induced experimentally in
mice when injected at the site of infection (14). N. sativa extract showed almost similar results to topical
mupirocin in the treatment of neonates with staphylococcal pustular skin infections with no side effects(15).
Microbial resistance to drugs is a common and important issue. Studies of the effects of N. sativa extracts in vitro
against resistant microorganisms, including resistant Staphylococcus aureus and Pseudomonas aeruginosa, showed
promising and good results against many multi-drug-resistant gram positive and gram negative bacteria (16 - 18).
Antiviral
N. sativa was found to enhance helper T cell (T4) and suppressor T cell (T8) ratio and increased natural killer (NK)
cell activity in healthy volunteers (1). Besides improvement in immunity, N. sativa extract had some inhibitory
effect on the human immune deficiency virus protease but the active principle(s) responsible for this activity was
not identified (19). Moreover, N. sativa oil when given intraperitoneally to mice infected with murine
cytomegalovirus for 10 days, the virus was undetectable in the liver and spleen, while it was still detectable in the
control mice. This action was considered to be related to increase in number and function of M-phi and CD4 +ve T
cells and increased production of INF-gamma (20).
Antifungal
Hanafi and Hatem (14) were the firsts to demonstrate the inhibitory effect of the diethyl-ether extract of N. sativa
extract against Candida albicans. The ether extract of N. sativa was reported to inhibit the growth of Candida
yeasts in several organs in experimental animal infections (21). Thymoquinone was also shown to inhibit in vitro
Aspergillus niger and Fusarium solani and the activity was comparable to amphotericin-B (22 - 24). It was reported
to be more effective than Amphotericin-B and griseofulvin against Scopulariopsis brevicaulis growth in vitro. There
was 100% inhibition of the growth of S. brevicaulis with thymoquinone 1mg/ml, while amphotericin-B 1mg/ml
inhibited only 70% growth. However, clotrimazole was much more effective than the above mentioned drugs, with
an MIC of 0.03mg/ml (25).
The ether extract of N. sativa was found to inhibit dermatophytes isolated from sheep skin infection (26).
Thymoquinone was shown to possess moderate activity against clinical isolates of the three main groups of
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dermatophytes: Trichophyton, Epidermophyton and Microsporum and the ether extract of N. sativa was also found
to be effective but in relatively higher concentrations (27). The MIC of thymoquinone against various
dermatophytes ranged from 0.125 - 0.25 mg/ml, while the ether extract inhibited 80-100% of the growth of most
dermatophytes at 40mg/ml. Proportionately, greater effect of thymoquinone than N. sativa extract points out to
that, the antifungal activity of N. sativa is primarily due to thymoquinone (27). In another study also
thymoquinone, thymohydroquinone and thymol demonstrated antifungal effect against many clinical isolates,
including dermatophytes, molds and yeasts at a concentration of 1mg/ ml (28). Using broth microdilution assay,
extract of N. sativa inhibited the growth of Madurella mycetomatis, an important causative fungus of mycetoma,
at a concentration as low as 1 ug/ml (29)
Antiparasitic
An ointment prepared from the alcoholic extract of N. sativa seeds was applied daily for 15 weeks to cutaneous
leishmaniasis produced experimentally in mice by a subcutaneous inoculation of Leishmania major at the dorsal
base of the tail. The morphology of the lesion and the body weight of mice were monitored daily. There was no
significant difference between the average weight of mice receiving N. sativa extract ointment and controls but
the lesion diameter and symptoms of inflammation were significantly lesser in the test group as compared to the
controls (30).
N. sativa seed was tested against miracidia, cercariae and adult worms of Schistosoma mansoni and showed strong
biocidal activity against all stages of the parasite, as well as an inhibitory effect on egg-laying of adult female
worms, indicating an antischistosomal potential of the N. sativa (31). In Schistosomiasis mansoni experimentally
infected mice, the antischistosomal activity of N. sativa oil was found to be comparable to prazequantel and when
given in combination with prazequantel there was potentiation of its effect (32).
Wound healing
N. sativa seed and its oil were found to promote wound healing in farm animals (33). Moreover, ether extract of N.
sativa seed applied topically onto staphylococcal-infected skin in mice enhanced healing by reducing total and
absolute differential WBC counts, local infection and inflammation, bacterial expansion and tissue impairment
(34). Using human gingival fibroblast as a monolayer, aqueous extract of N. sativa exhibited low free radical
scavenging activity and induced gingival fibroblast proliferation with accelerated wound closure activity despite its
non-significant effect on collagen synthesis (35). It also resulted in elevation of basic fibroblast growth factor and
transforming growth factor beta (35).
Anti-inflammatory effect
Psoriasis
The ethanolic extract of N. sativa seed was evaluated for antipsoriatic activity in vivo by using mouse tail model for
psoriasis and in vitro by using sulphorhodamine B assay employing HaCaT human keratinocyte cell lines (36).
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Significant epidermal differentiation was produced by the ethalonic extract of N. sativa , 71.36±2.64%. In the
negative control the epidermal differentiation was 17.30±4.09% and in the positive control (tazarotene 0.1%) was
90.03±2.00%. The antiproliferant activity of the ethanolic extract of N. sativa was good, IC50 value of 239 μg/ml,
as compared to that of the positive control, asiaticoside, which showed potent activity with IC50 value of 20.13
μg/ml.
Acne vulgaris
In a clinical study (37), N. sativa oil lotion 10% significantly reduced mean lesion count of papules and pustules
after 2 months of therapy. In the test group, the response to treatment was graded as good in 58%, moderate in
35% and no response in 7%. The satisfaction of patients with treatment was found to be full in 67%, partial in 28%,
and no satisfaction in 5%. While in the control group, the lesions showed no significant reduction after 2 months
and the response to treatment was good in 8%, moderate in 34%, and no response in 58%. The satisfaction of
patients with treatment in this group was full in 8%, partial in 24%, and no satisfaction in 68% . There were no side
effects in the group treated with N. sativa oil lotion 10% . The authors attributed the results to the antimicrobial,
immunomodulatory and anti-inflammatory effects of N. sativa oil. The molecular mechanisms of anti-inflammatory
and antioxidative activities of thymoquinone, the most abundant active principle of N. sativa had been studied.
Pretreatment of female HR-1 hairless mouse skin with thymoquinone attenuated 12-O-tetradecanoylphorbol-13-
acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2). Thymoquinone diminished nuclear translocation
and the DNA binding of nuclear factor-kappa-B (NF-κB) via the blockade of phosphorylation and subsequent
degradation of IκBα in TPA-treated mouse skin. Thymoquinone also attenuated the phosphorylation of Akt, c-Jun-
N-terminal kinase and p38 mitogen-activated protein kinase, but not that of extracellular signal-regulated kinase-
1/2. Moreover, topical application of thymoquinone induced the expression of hemeoxygenase-1, NAD(P)H-
quinoneoxidoreductase-1, glutathione-S-transferase and glutamate cysteine ligase in mouse skin (38).
Similar anti-inflammatory effect of N. sativa fixed oil and thymoquinone has also been reported earlier by
Houghton et al (39). The effect was demonstrated via the dose-dependent decrease in the formation of
thromboxane B2 and leukotriene B4 showing the inhibition of cycloxygenase and 5-lipooxygenase pathways of
arachidonate metabolism in rat peritoneal leukocytes.
Vitiligo
Lyophilized seed extract of N. sativa and its active ingredient, thymoquinone, showed significant skin darkening on
the isolated melanophores of the wall lizard (40). The pigment cells when exposed to the extract or thymoquinone
responded by distinct dispersion of melanin leading to skin darkening. The melanin dispersal effect was
antagonized by anticholinergic drugs, atropine and hyoscine, and potentiated by an anticholinesterase agent,
neostigmine. The authors suggested that cholinergic mechanisms of muscarinic nature are involved in the melanin
dispersion (40). In a randomized double blind clinical study, patients applyied N. sativa oil to lesions of vitiligo
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twice daily for six months had a significant decrease in the vitiligo area scoring index with no significant side effects
(41).
Hypersensitivity reactions
Earlier, carbonyl fraction of N. sativa and its active components, thymoquinone and nigellone were shown to
counter the manifestations of allergic reactions; inhibition of histamine release from mast cells (42), protection
from histamine-induced bronchospasm in guinea pigs (43) and decreases in the lung eosinophilia, elevated Th2
cytokines and raised IgE and IgG1 antibodies in a mouse model of allergic asthma induced by ovalbumin (44).
Recently, a clinical study was conducted to compare the efficacy of Nigella, Betamethasone and Eucerin ointments
applied topically twice daily for 4 weeks in new cases of hand eczema. Changes in the severity of eczema and life
quality were assessed by Hand Eczema Severity index (HECSI) and Dermatology Life Quality Index (DLQI),
respectively. Nigella and Betamethasone showed rapid improvement in the hand eczema and the quality of life as
compared to Eucerin. No significant difference was detected in the mean HECSI and DLQI scores of the N. sativa
and Betamethasone groups, indicating to the possibility that, N. sativa had same efficacy as betamethasone in the
improvement of hand eczema and life quality (45).
Skin cancer
The anticancer activity of N. sativa was revealed, for the first time, when an enhancement of the natural killer (NK)
cell activity was observed in advanced cancer patients receiving multimodality immunotherapy program in which
N. sativa seed was one of the components (1). Regarding dermatology, Solami et al (46) were first to investigate
the antineoplastic effect of N. sativa. They reported that the topical application of N. sativa and Crocus sativus
extracts inhibited two-stage initiation / promotion of [dimethylbenz [a] anthracene (DMBA) / croton oil] induced
skin carcinogenesis in mice, delayed the onset of papilloma formation and reduced the number of papillomas per
mouse. Later, the protective effect of bee honey and Nigella was studied on the oxidative stress and
carcinogenesis induced by methylnitrosourea (MNU) in Sprague Dawely rats. It was observed that MNU produced
oxidative stresses ranging from severe inflammatory reaction in lung and skin to colon adenocarcinoma in four out
of six animals. The serum malondialdehyde (MDA) and nitric oxide (NO) were also raised. Treatment with N. sativa
seed given orally protected against MNU-induced oxidative stress and carcinogenesis by 80% (12/15), whereas
honey and N. sativa seed together protected 100% (12/12); and serum MDA and NO also significantly decreased in
both cases compared to active controls (47).
In another study, antineoplastic activity of thymoquinone was investigated using mouse keratinocytes, papilloma
(SP-1) and spindle-17 carcinoma cells. In SP-1 cells thymoquinone induced G0/G1 cell-cycle arrest, which
correlated with sharp increases in the expression of the cyclin-dependent kinase inhibitor p16 and a decrease in
cyclin D1 protein expression. While in spindle 17 cells, G2/M cell-cycle arrest was noticed, this was associated with
an increase in the expression of the tumor suppressor protein p53 and a decrease in cyclin B1 protein. At longer
times of incubation, thymoquinone induced apoptosis in both cell lines by remarkably increasing the ratio of
Bax/Bcl-2 protein expression and decreasing Bcl-xL protein. These findings support a potential role for
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thymoquinone as a chemopreventive agent, particularly at the early stages of skin tumorigenesis (48). Antitumor
activity of thymoquinone and thymohydroquinone was also demonstrated using tumor cell lines (squamous cell
carcinoma, SCC VII) and fibrosarcoma, FsaR) and murine tumor models of fibrosarcoma and squamous cell
carcinoma (49).
Thymoquinone and diosgenin, the active ingredients obtained from N. sativa and fenugreek (Trigonella
foenumgraecum), respectively, were shown to exert potent bioactivity against squamous cell carcinoma in vitro.
They inhibited cell proliferation and induced cytotoxicity in A431 and Hep2 cells. These agents induced apoptosis
by increasing the sub-G1 population, LIVE/DEAD cytotoxicity, chromatin condensation, DNA laddering and TUNEL-
positive cells. There was also an increase in Bax/Bcl-2 ratio, activation of cell proliferation of caspases and cleavage
of poly ADP ribose polymerase in the treated cells. In combination, thymoquinone and diosgenin had synergistic
effects, resulting in cell viability as low as 10%. In a mouse xeno-graft model, a combination of thymoquinone and
diosgenin significantly reduced tumor volume, mass and increased apoptosis (50).
Using an in vitro cell migration assay, Ahmad et al (51) found that, thymoquinone inhibited the migration of both
human and mouse melanoma cells. The inhibition of metastasis by thymoquinone was also observed in vivo in
B16F10 mouse melanoma model and was accompanied by a decrease in expression of NLRP3 (NACHT, LRR, and
pyrin domain-containing protein 3) inflammasome which resulted in decreased proteolytic cleavage of caspase-1.
Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1β and IL-18. Thymoquinone also inhibited
NF-κB activity in mouse melanoma cells and reactive oxygen species and the later in turn resulted in partial
inactivation of NLRP3 inflammasome. The authors suggested that, thymoquinone can be a potential
immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention
of metastatic melanoma (51).
Percutaneous absorption
The effect of N. sativa oil on the percutaneous absorption of model lipophilic drug-carvedilol was investigated
using excised rat abdominal skin (52). N. sativa oil in 5% v/v had high degree of enhancing permeation as indicated
by transdermal flux, permeability coefficient and enhancement factor. Employing differential scanning calorimetry,
Fourier transform infrared and histopathology, N. sativa oil in 5% v/v, was found to work by extracting lipids from
stratum corneum and by loosening the hydrogen bonds between ceramides with subsequent fluidization of the
lipid bilayer. The increased permeability of the lipophilic drug-carvedilol was considered to be due to increased
diffusivity through the stratum corneum under the influence of N. sativa oil. It was postulated that, the higher
content of linoleic acid and other unsaturated fatty acids in N. sativa oil was responsible for the enhancement of in
vitro percutaneous absorption of the drug (53).
Cosmetic application
Using pH meter, corneometer, tewameter, methyl nicotinate model of micro-inflammation in human skin, and
tape stripping of the stratum corneumin, the in vivo and ex vivo properties of emulsions with the seedcake extracts
of N. sativa have been evaluated (54). Emulsions with Borago officinalis, and Nigella sativa seedcakes significantly
8
reduced skin irritation and improved the skin hydration and epidermal barrier function as compared with placebo.
The authors suggested the potential use of seedcakes in anti-aging, moisturizing, mitigating, and protective
cosmetics due to their antioxidant and anti-inflammatory activities.
Cutaneous side effects
Contact dermatitis developed after the application of ointment made from the N. sativa seed oil but it could have
been due to some impurity in the commercial black seed oil (55). Bullous drug eruption with sub-epidermal
detachment and necrosis of the epidermal surface has been reported in a 53 – year – old woman after two weeks
of applying N. sativa oil to her skin and ingesting it as well (56)
Conclusion
The published original research articles on the effects of N. sativa and its ingredients strongly indicate to
pharmacological potential in dermatology. Standard methods of drug development are needed to formulate
topical therapy for use in dermatology.
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