Article contributed by SHAHNAS BINTI OLI MOHAMED
Background : B. Pharm (Hons), USM Penang; IMBA, University South Australia, Australia
Further clarificataion on this article can be obtained from the contributor at email email@example.com
NIGELLA SATIVA (HABBATUS SAWDAH)
Nigella sativa has been used for medicinal purposes for centuries, both as an herb and pressed into oil, in Asia, Middle East, and Africa. It has been traditionally used for a variety of conditions and treatments related to respiratory health, stomach and intestinal health, kidney and liver function, circulatory and immune system support, and for general well-being. It is also used for scorpion and spider stings and bites of snake, cat and dog. In addition, it is used as a flavoring additive to bread and prickles (1, 2). In Islam, it is regarded as one of the greatest forms of healing medicine available. Prophet Muhammad once stated that the black seed can heal every disease—except death—as recounted in the following hadith:
“Narrated Khalid bin Sa’d: We went out and Ghalib bin Abjar was accompanying us. He fell ill on the way and when we arrived at Medina he was still sick. Ibn Abi ‘Atiq came to visit him and said to us, “Treat him with black cumin. Take five or seven seeds and crush them (mix the powder with oil) and drop the resulting mixture into both nostrils, for ‘Aisha has narrated to me that she heard the Prophet saying, ‘This black cumin is healing for all diseases except As-Sam.’ ’Aisha said, ‘What is As-Sam?’ He said, ‘Death.’ ” (Bukhari)
Ibn Sina, most famous for his volumes called The Canon of Medicine, refers to nigella as the seed that stimulates the body’s energy and helps recovery from fatigue and dispiritedness. It is also included in the list of natural drugs of ‘Tibb-e-Nabavi‘, or “Medicine of the Prophet (Muhammad)”, according to the tradition “hold onto the use of the black seeds for in it is healing for all diseases except death” [Sahih Bukhari vol. 7 book 71 # 592].
The multiple use of N. sativa in the folk medicine encouraged many investigators to isolate the possible active components and to conduct in vivo and in vitro studies on laboratory animals and human beings in order to understand its pharmacological actions. These include, immune stimulation1, anti-inflammatory (3), anti-cancer (4), anti-microbial (5, 6), anti-parasitic (7), anti-oxidant (8, 9), and hypoglycemic effects (10, 11), etc.
Nigella sativa seeds are a good source of oil and protein. Proximate analysis of the seeds showed a composition of 20.85% protein, 38.20% fat, 4.64% moisture, 4.37% ash, 7.94% crude fibre and 31.94% total carbohydrate (82). No trace of lead, cadmium and arsenic were found in the seeds. The predominant elements present were potassium, phosphorus, sodium and iron while zinc, calcium, magnesium, manganese and copper were found at lower levels (82). The seeds may potentially be an important nutritional source as the content of essential amino acids contributes to about 30% of the total protein content while about 84% of the fatty acids are composed of unsaturated fatty acids, predominantly linoleic and oleic acids (82, 83).
Oil extracts of the seeds also contain significant amounts of sterols. β-Sitosterol was the dominant sterol (69%); while campesterol and stigmasterol constitute 12% and 19%, respectively of the total sterols (83). The seed oil was found to be rich in polyphenols (1,744 µg/g) and tocopherols (340 µg/g of total a-, b- and g-isomers) (83). N. sativa seeds contain 36%-38% fixed oils, proteins, alkaloids, saponins and 0.4% – 2.5 % essential oil (84). The fixed oil is composed mainly of fatty acids, namely, linoleic (C18:2), oleic (C18:1) and palmitic acids (C16:0) (82, 85, 86, 87, 88). Many components were characterized from the essential oil, but the major ones were thymoquinone (27.8%-57.0%), ρ-cymene (7.1%-15.5%), carvacrol (5.8%-11.6%), t-anethole (0.25%-2.3%), 4-terpineol (2.0%-6.6%) and longifoline (1.0%-8.0%) (84, 90).
Thymoquinone is the main active constituent of the volatile oil extracted from Nigella sativa (84, 90, 91). Good quality control methods were used for quantifying the pharmacological actives thymoquinone, dithymoquinone, thymohydroquinone and thymol, in both the seed oils and extracts of N.sativa. (92) Other active principles were nigellone, which was isolated from the volatile oil fraction and was found useful in the treatment of bronchial athma (93), and nigellidine which contains an indazole nucleus (94). Three flavonoid glycosides and triterpene saponins were also identified from Nigella sativa (95, 96).
Effect on Immune System:
As a natural remedy people take N. sativa seed or oil as a promoter of good health and for the prophylaxis of common cold and asthma. In view of that El-Kadi and Kandil1 investigated the effect of N. sativa on immune system and reported that the administration of 1g twice daily in human volunteers enhanced immune functions as manifested by improved helper T cell (T4) to suppressor T cell (T8) ratio and an improved natural killer cell activity. However, there was a decrease in the immune globulin (IgA, IgG and IgM) levels.
Moreover, Haq et al (27) noticed that N. sativa enhanced the production of interleukin-3 by human lymphocytes when cultured with pooled allogenic cells or without any added stimulator. They also observed an increase in interleukin-1 beta (IL-1b) suggesting that N. sativa has an effect on macrophages as well. In another study on mixed lymphocyte culture, Haq et al (28) observed that whole N. sativa seeds and its purified proteins demonstrated stimulatory as well as suppressive effects depending upon the donor and the concentration used.
Stimulant effect was observed with fractionated N. sativa proteins (P1 and P2) with a maximum effect at 10 ug/ml. Suppressive effect was observed with N. sativa seeds and high concentrations of all of its four proteins when lymphocytes were activated with poked-weed mitogen. In culture medium with non-activated peripheral blood mononuclear cells and with allogenic cells whole N. sativa produced large quantities of IL-1 beta, but no effect was seen on IL-4 secretion.
The effect on IL-8 production was variable. However, a stimulatory effect of whole N. sativa and its fractionated proteins was noticed on the production of TNF-a in both non-activated and mitogen activated cells. The ethyl-acetate chromatographic fraction of ethanolic extract of N. sativa has also been reported to potenciate cellular immune responses (29).
Anti-inflammatory and Analgesic Effect:
In Saudi Arabia and neighbouring countries N. sativa oil is used as a topical treatment for pain and stiffness in joints. This indication together with its use in bronchial asthma suggested for the investigation of analgesic and anti-inflammatory effects of N. sativa. Houghton et al (3) reported that crude fixed oil of N. sativa and an active principle, thymoquinone, inhibited cycloxygenase and 5-lipooxygenase pathways of arachidonate metabolism in rat peritoneal leukocytes. The effect was demonstrated via the dose-dependent inhibition of the formation of thromboxane B2 and leukotriene B4.
This effect was later confirmed in experimental animal studies conducted by Mutabagani and El-Mahdy (30) using N. sativa volatile oil and Al-Ghamdi (31) using aqueous suspension of N. sativa crushed seeds. In both studies formation of edema in rat hind paw was inhibited and these effects were comparable to those of indomethacin and aspirin, respectively. Al-Ghamdi (31) also reported an analgesic effect of aqueous suspension of N. sativa seeds, comparable to aspirin, as measured by hot plate test conducted in rats. However the suspension did not relieve yeast-induced pyrexia in rats.
The mechanism of anti-inflammatory and analgesic effects seems to be related to the inhibition of eicosanoid synthesis as suggested by the study of Houghton et al (3). Another possibility for the analgesic action could be the activation of supraspinal mu (1)- and kappa-opioid receptors subtypes, as elicited by the antagonistic effect of naloxone, naloxonazine and nor-binaltorphimine to antinociceptive effects of N. sativa oil and thymoquinone (32).
The anticancer activity of N. sativa was first revealed by El-Kadi and Kandil (1) who observed enhancement of natural killer (NK) cell activity ranging from 200-300% in advanced cancer patients receiving multimodality immunotherapy programme in which N. sativa was one of the components. Later on, the anti-cancer effect ofN. sativa was investigated both in vitro using cancer cell lines and in vivo using animal models.
Topical application of N. sativa and Crocus sativus extracts inhibited two-stage initiation/promotion (dimethylbenz-a-anthracene/croton oil) of skin carcinigenesis in mice by delaying the onset of papilloma formation and reducing the number of papillomas per mouse. These extracts also restricted 20-methylcholanthrene induced soft tissue sarcomas in mice4. Moreover, an active principle of N. sativacontaining fatty acids demonstrated, in vitro, 50% cytotoxic activities against Ehrilch ascites carcinoma (EAC), Dalton’s lymphoma ascites and sarcoma-180 cells and, in vivo, completely inhibited EAC tumour development in mice (33).
Thymoquinone and dithymoquinone, active principles of N. sativa, had cytotoxic effect against parental and multi-drug resistant human tumour cell lines which were over 10-fold more resistant to doxorubicin and etoposide (34). Similarly, thymoquinone reduced the incidence and multiplicity of benzo-a-pyrene induced forestomach tumour in female Swiss albino mice by 70% and 67%, respectively (35). Ethyl-acetate column chromatographic fraction (CC-5) of ethanolic extract of N. sativa also showed cytotoxic effect against different classes of cancer cell lines, such as, Hep G2, Molt4 and Lewis lung carcinoma cells (29).
More recently, CC-5 and alpha-hedrin (AH), which were isolated from CC-5, produced significant dose dependent tumour inhibition rate comparable to cyclophosphamide treated group (24). Similarly, thymoquinine inhibited 20-methylcholanthrene-induced fibrosarcoma in mice (35).
Anti-Microbial and Anti-Parasitic Actions:
The anti-bacterial effect of the phenolic fraction of N. sativa oil was first reported by Topozada et al (5). Thymohydroquinone was later isolated by El-Fatatry (6) from the volatile oil of N. sativa and found to have high activity against gram-positive microorganisms. Hanafi and Hatem (36) studied the antimicrobial effect of diethyl-ether extract of N. sativa and reported that it had a concentration dependent inhibition of gram-positive bacteria (represented by Staphylococcus aureus) and gram-negative bacteria (represented byPseudomonas aerogenosa and Escherichia coli).
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. In addition, the extract was found to have a concentration dependent inhibitory effect against pathogenic yeast, Candida albicans. Recently, crude extracts of N. sativa were reported to have a promising effect on multi-antibiotic resistant organisms including gram-positive and gram- negative bacteria (37). Intra-peritoneal administration of N. sativa oil strikingly inhibited the virus titer in spleen and liver of mice infected with murine cytomegalovirus38. This action was possibly mediated by increasing the number and function of M & phi as well as IFN-g production.
Akhtar and Riffat (7) investigated the anti-cestodal effect of N. sativa seeds and its ethanolic extract when given orally to infected children. Both were effective in reducing the percentage of faecal eggs per gram counts and the effect was comparable to niclosamide. Moreover, N. sativa menthol extract (1ml/kg) and powder (200 mg/kg) showed high efficacy, comparable to Hapadex (netobimin, 20 mg/kg), against rumin fluke (Paramphistomum) in sheep39 and Nigella sativa oil also prevented liver damage induced bySchistosoma mansoni infection in mice (40).
N. sativa extracts and some of its active principles, like thymoquinone, have been shown to possess protective effect against haematological, hepatic, renal and other toxicities induced by anti-cancer drugs and some toxins. For example, N. sativa extract prevented the decreases in haemoglobin level and leucocyte count caused by cisplatin in mice (8). Thymoquinon and fixed oil of N. sativa were also reported to inhibit non-enzymatic peroxidation in ox brain phospholipid liposomes (3).
N. sativa along with cysteine, vitamin E and Crocus sativus protected cisplatin-induced haematological, hepatic and renal toxicities (41). Thymoquinone protected isolated rat hepatocytes from ter-butyl-hydro-peroxide-induced toxicity (42). Thymoquinone also showed hepatoprotective effect against CCl4 – induced toxicity in mice (43). El-Dakhakhany et al (44) have also reported the protective effect of N. sativa oil against CCl4 and D-galactosamine induced hepatic toxicity in rats. In these studies protection from liver toxicity was measured as a significant decrease in serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase, etc and a significant increase in glutathione reductase.
Badary et al (35, 45) observed the protective effect of thymoquinone on ifosfamide–induced Fanconi syndrome in mice and doxorubicin-induced hyperlipidemic nephropathy in rats, respectively, manifested as a significant improvement of phosphaturia, glucosuria, and elevated serum creatinine and urea as well as a significantly improvement of renal glutathione depletion and lipid peroxide accumulation.
Furthermore, Burits and Bucar46 found that N. sativa essential oil and its four constituents (thymoquinone, carvacrol, t-anethol and 4-terpineol) had anti-oxidant effect in different chemical assays, like diphenylpicrylhydracyl assay for non-specific hydrogen atom or electron donating activity. They also observed OH-radical scavenging property in the assay for non-enzymatic lipid peroxidation in liposomes and the deoxy-ribose degredation assay. More recently, Turkdogan et al (47) reported the protective action of N. sativa for carbon tetrachloride induced liver fibrosis and cirrhosis in rabbits, as well as El-Sherbeny (48) reported the protective effect of N. sativa against the genotoxic action of an herbicide, 2, 4-D.
Anti-Histaminic Action :
The antihistaminic effect was first investigated by El-Dakhakhany (49) who reported the protective action of thymoquinone and carbonyl fraction of N. sativa against histamine-induced bronchospasm in guinea pigs. Furthermore, in an in vitro study, Chakarvarti (50) demonstrated that nigellone, isolated from N. sativa, effectively inhibited the release of histamine from mast cells, possibly through decrease in intracellular calcium and inhibition of protein kinase C. These effects together with analgesic and anti-inflammatory actions, perhaps, can be correlated with the use of N. sativa in eczema and asthma, for scorpion and spider stings and for the bites of cat, dog and snake, recommended in the folk medicine (2).
Effects on the Respiratory System:
In Saudi Arabia and neighbouring countries N. sativa seeds and oil are commonly used for the treatment of asthma. Nigellone (a carbonyl polymer of thymoquinone) proved to be an excellent prophylactic agent for both bronchial asthma and asthmatic bronchitis and was more effective in children than adults (51, 52). Sayed (53) has also reported the use of N. sativa in asthma in the traditional medicine. However, El-Tahir et al (54) observed that N. sativa volatile oil induced dose dependent increase in the respiratory rate and the intra-tracheal pressure, which were antagonized by mepyramine, atropine and reserpine but not by indomethacin, diethyl-carbamazine or hydrcortisone.
A central mechanism was suggested for these effects. Apparently, these observations seem to be in contrary to the antihistaminic effect reported by El-Dakhakhany (49) and Chakarvart (50) and its use in the folk medicine for asthma. However, in a later study, aqueous extract of N. sativa competitively and the macerated extract non-competitively antagonized methacholine induced contractions of isolated guinea-pig tracheal chain (55). Similarly, crude extract of N. sativa has also been shown to cause relaxation of carbachol –, histamine – and K + – induced contractions of isolated guinea-pig trachea (56).
Effect on Cardiovascular System:
In Arabian folk medicine whole seeds of N. sativa alone or in combination with honey or garlic are promoted for the treatment of hypertension, which drew the attention of EL-Tahir et al (57) to investigate the effects ofN. sativa on the cardiovascular system. Volatile oil and thymoquinone produced a dose dependent decrease in the arterial blood pressure and the heart rate. These effects were significantly antagonized by atropine, cyproheptadine, hexamethonium and spinal pithing. However, reserpine only antagonized the effects of low doses of volatile oil but not of thymoquinone.
They suggested that these effects were centrally mediated, mainly via the involvement of both the 5-hydroxytryptaminergic and muscarinic mechanisms. Similarly, an oral dose of 0.6ml/kg/day of N. sativaextract produced a significant hypotensive effect in spontaneously hypertensive rats comparable to that of 0.5 mg/kg/day of oral nifedipine (58, 59). This effect was concluded to be partially due to the diuretic effect of N. sativa, which was comparable to 0.5 mg/kg/day furosemide or by other mechanisms as mentioned above.
Effect on Genito-Urinary System:
In Unani medicie N. sativa is promoted for the treatment of oligomenorrhoea, to induce menstruation and to treat infertility (2). El-Naggar and El-Deib (60) reported that N. sativa crude oil induced uterine contractions both in vivo in pregnant rabbits and in vitro of non-pregnant rat uteri. Similarly, Keshri et al (61) found that the hexane extract of N. sativa exhibited mild uterotropic activity and prevented pregnancy in rats when given on day 1-10 post-coitum. On the contrary, Aqel and Shaheen (62) reported that volatile oil of N. sativa inhibited spontaneous contractions of rat and guinea pig uterine smooth muscle and those induced by oxytocin.
Similarly, treatment of pregnant rats with fixed oil of N. sativa for 2 weeks significantly suppressed PGE2 and oxytocin – induced contractions of isolated rat uteri treated with diethylstilboesterol, suggesting the potential use of N. sativa oil in the uterine disturbances associated with prostaglandin and oxytocin induced increased contractility e.g. some dysmenorrhoeas, premature deliveries and habitual abortions (63). These differences may be due to the different doses, preparations and the animal species used.
Effect on Gastro-Intestinal Tract:
In Unani medicine N. sativa is used for stomachache and as a digestive, carminative, laxative and anti-jaundice1. Oral N. sativa powder was reported to relieve flatulence by Chopra et al (64). While Nigellone, an active principle of N. sativa was found to antagonize histamine induced contractions of guinea pig intestine. In addition, Mahfouz et al (52) and El-Dakhakhani (65) reported a choleretic effect of N. sativa oil and its active principles (thymoquinone, thymohydroquinone and dithymoquinone), respectively.
El-Dakhakhani et al (66) investigated the effect of N. sativa oil on gastric secretion and ethanol-induced ulcer in rats. Significant increase in mucin content, glutathione level as well as a significant decrease in mucosal histamine content and ulcer formation, with a protection ratio of 53.56 %, was found in the N. sativa oil pretreated group. More recently, the crude extract of N. sativa was shown to cause a dose –dependent (0.1–3.0 mg/ml) relaxation of spontaneous contractions of rabbit jejunum as well as inhibition of K + – induced contractions in a similar dose range, suggestive of calcium channel blockade (56).
Al-Awadi and Gumma (10) have reported the use of a plant mixture containing N. sativa, Myrr, GumOlybanum, Gum Asafoetida and Aloe by diabetics in Kuwait. They confirmed the blood glucose lowering effect of N. sativa, in combination with other herbs in rats. The mechanism of action was later investigated and appeared to be due to the inhibition of hepatic gluconeogenesis (67).
The volatile oil of N. sativa alone also produced a significant hypoglycemic effect on normal and alloxan-induced diabetic rabbits without changes in insulin levels (68). The hypoglycemic effect of N. sativa in combination with other herbs on alloxan-induced diabetic rats was also reported by Eskander et al (69) and El-Shabrawy and Nada (70). Furthermore, Bamosa et al (11) reported a significant decrease in blood sugar of healthy human volunteers treated with 1 gram of N. sativa capsules twice daily.
Effect on Blood:
In Kuwait some people use extract of N. sativa with natural fat for epistaxis. In view of that the petroleum ether extract of N. sativa was studied for its action on blood coagulation and was reported to shorten the whole blood clotting time, plasma clot time and kaolin-cephalin clotting time of male rabbits when compared to control. In addition, a significant shortening of bleeding time in rats was also observed.
However, there were no significant effects on the thrombin time or prothrombin time but the partial thromboplastin time was shortened while euglobulin time was prolonged (71). In contrast, N. sativa fixed oil suppressed adenosine diphosphate – induced platelet aggregation in both normal and diabetic rats (63). Similarly, in a recent study it was observed that the menthol soluble components of N. sativa oil including 2-(2-methoxypropyl)-5-methyl-1, 4-benzenediol, thymol and carvacrol as well as (8) other related compounds had very strong inhibitory effect on arachidonic acid -induced platelet aggregation. This platelet aggregation inhibitory effect was more potent than that of aspirin (72).
Bamosa et al (11) reported a pattern of decreased levels of cholesterol and triglycerides (on days 7 and 14) of healthy human volunteers treated with 1 gram of N. sativa capsules twice daily. This effect was later confirmed by El-Dakhakhani et al (66 ) using N. sativa oil (800 mg/kg orally for 4 weeks) in rats showing a significant decrease in serum total cholesterol, low density lipoprotein and triglycerides and an elevation of serum high density lipoprotein level.
More recently, N. sativa oil in rats has been shown to decrease the serum cholesterol, triglycerides and glucose levels as well as the counts of leukocytes and platelets by 15.5, 22, 16.5, 35 and 32%, respectively, while haematocrit and haemoglobin levels increased by 6.4 and 17.4%, respectively (58). However, Al-Jishi (2) did not find any changes in blood cells when N. sativa was given to normal rats.
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