INTRODUCTION:

The term Nigella comes from Latin word ‘Niger’ which means black, mainly to seeds and considered as flowering species. It is also known as funnel flower, kalonji, black cumin, black caraway, devil in the bush, damascene, melanthion, wild onion seed etc [1]. This plant is native to south and southwestern countries of Asia e.g. India, Europe and Arabian, which is 20-30cm long, having linear type leaves and delicate type blue to white color flowers consist of five-ten petals [2]. The essential part of this medicinal herb is seed which is treated as blessed seed ‘remedies for all disease except death’ in some religious area [3].

According to Hippocrates and Discorides, this herb is known as the Melanthion which seeds and oil is used in many traditional remedies over 2000 years [4]. In the most famous book of Avicenna called The Canon of Medicine, it was written that N. Sativa seeds stimulate the body’s energy and recover from fatigue. In Medicine of the Prophet, nigella sativa seed used for healing all disease. In Indian system of medicine, N. sativa seeds used for various therapeutic activities like astringent, stimulant, diuretic, anthelmintic, jaundice, fever, dyspepsia, paralysis, piles also in skin disease (Fig. 1) [5].

Fig. 1: Negilla sativa

The herb is 45 cm in height where Leaves are 2.5-5.0 cm long, Flowers are 2.0-2.5 cm in size, capsule 1.2 cm long, seeds are generally black in color and are oblong, angular, flattened, funnel shaped, small, it is about 0.2 cm long and 0.1 cm wide. The propagation of plant is also carried out by callus culture in vitro from root, stem and leaves. Seed is externally black and internally white which is a dicotyledonous type, small trigonus, angular, regulosetubercular. It is bitter in taste and the odour is astringent. The transvers sections of seed have single layered epidermis which is 2-4 layers thick parenchymatous cells, and covered by externally papillose cuticle [6].

ACTIVE COMPOUNDS OF NEGILLA SATIVA:

N. sativa contains various phytochemical constituents such as alkaloids, phenols, flavonoids, glycosides, terpenoids and steroids. The furthermost active constituents of N. sativa are thymohydroquinone, p-cymene, dithymoquinone, thymoquinone, carvacrol, sesquiterpene longifolene. Black seed of N. sativa contains alkaloids like nigellicimine, isoquinoline, pyrazol and nigellicimine-N-oxide. Apart from alkaloid seed also contains pentacyclic triterpene, alpha-hederin, protein, carbohydrates, crude fibre, fat and saponin. These constituents are also accountable for anticancer agent [7,8]. N. sativa seed is also a good source of vitamins and minerals such as P, Zn, Fe, Cu etc. N. sativa shoot and root are reported to have vanillic acid. The pharmacological activities of N. sativa are due to its quinine constituents like thymoquinone and dithymoquinone [7,9]. The seed is also accounted to have linoleic acid, saturated fatty acids (palmitic, stearic acid), eicodadienoic acid, oleic acid and dihomolinoleic acid [10,11]. The number of researchers also reported that N. sativa contains various components like campesterol, citrostadienol, gramisterol, stigmastanol, β-amyrin, cycloartenol, tirucallol, avenasterol-5-ene methylene-cycloartanol, nigellone and 24-methylene-cycloartanol [12-16].

TRADITIONAL USE:

N. sativa is a traditional Indian medicinal herbs which was used to cure several diseases like fever, conjunctivitis, diarrhoea, anorexia, dyspepsia, bronchitis, asthma, inflammatory diseases and haemorrhage. It is also used in several diseases and condition related to digestive tract, cardio vascular system, kidney and liver function as well as immune system support. N. sativa has been used as stimulant, emmenagogue, appetizer, pungent, anthelmintic, pungent, deodorant, carminative, purgative, expectorant, febrifuge, deodorant etc. The seed oil of the N. sativa is also used as local anesthetic and antiseptic. One of the tee study revealed that tincture is also useful to control dysmenorrhoea and amenorrhoea, diarrhoea, loss of appetite [17,18].

Pharmacological effect of N. sativa:

Recently, new scientific techniques have been taken care into consideration to carried out pharmacological activity of N. sativa for its cure against multiple ailments and disorders. There are some of the following important pharmacological effects of N. sativa plant.

Antibacterial activity:

N. Sativa seeds possess antibacterial activity and inhibition of growth of Staphylococcus aureus proved antibacterial activity of seeds which was studied by using modified paper in a disc diffusion method [19]. Its antibacterial activity are also shown in human pathogenic bacteria such as Staphylococcus [20]. N. sativa shown some activity against Helicobacter Pylori in patients who are suffering from non-ulcer dyspepsia and also shown more activity against gram negative bacteria rather than gram positive bacteria. Ethanolic extract of N. sativa showed antibacterial activity against Staphylococcus aureus [21]. N. sativa seeds also have anti-helicobacter pylori activity [22].

Antifungal activity:

Methanolic extract of N. sativa followed by chloroform extract shows antifungal activity against Candida albicans whereas aqueous extracts did not show antifungal activity, Ether extract of N. sativa possess anti-dermatophyte activity and ant yeast activity [23]. In a study, a patient having eczema which is pruritic papulovesicular dermatitis, N. sativa ointment showed potential effect as betamethasone ointment [24]. Another one patient was suffering from vitiligo and patients were administered N. sativa oil and fish oil for twice a day for 6 months. The result indicates that N. sativa oil is more effective than fish oil [25]. Ether extract of N. sativa showed antidermatophyte activity against dermatophytes [26].

Anticancer activity:

Administration of N. sativa extract shows anticancer activity in pancreas and liver. N. sativa also exhibit enhancement of CD8+ T cells. More research when carried out upon this plant showed, that lipid extract of N. sativa is cytotoxic to MCF-7 cells while aqueous extract exhibit cytotoxicity effect on high concentration (50mg/ml) [27, 28].

Hepatoprotective effect:

Administration of N. sativa oil (80mg/kg/day) for one week with simultaneous drug therapy on methotrexate, reduces hepatotoxicity and increase the survival rate of patient having liver injury [29]. The methanolic extract of N. sativa when administered for 2 weeks (1g/kg) showed hepatoprotection as well as ameliorate liver enzymes like serum glutamic pyruvic transaminase (SGPT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin [30].

Antioxidant activity:

Methanolic extract of N. sativa seed possesses significant antioxidant properties [31]. Active constituents of N. sativa like thymoquinone possess antioxidant and antiarthritic activity against collagen induced arthritis in albino rats. Oral administration of thymoquinone significantly decreased pro-inflammatory mediators [32]. The methanolic extracts of N. sativa (shoots, roots and seeds) possess antioxidant activity.

Antidiabetic activity:

The antidiabetic activity of N. sativa was evaluated by single administration of streptozocin (STZ) (65 mg/kg) induced in rat. N. sativa extract significantly decreased tissue malondialdehyde (MDA and serum glucose level and significantly increased serum insulin and tissue superoxide dismutase (SOD). N. sativa possess anti-diabetic effect. This effect may be due to protective action of N. sativa to β-cells against oxidative stress [33]. Thymoquinone (20, 40, 80 mg/kg) were administred for 45 continual days, showed anti-diabetic effect. However, there was dose dependency was seen against streptozocin induced rats. It has also been noticed that N. sativa showed the synergistic effect which improving biomechanical behaviour. It also potentiates the insulin-dependent diabetic rats [34].

Anti-inflammatory effect and analgesic effect:

Aqueous extract of N.sativa exhibit anti-inflammatory and analgesic activity. The anti-inflammatory activity is due to the presence of main constituent thymoquinone [35].

Immunomodulatory activity:

N. sativa aqueous extract significantly increases splenocyte proliferation and also supress the secretion of nitric oxide (NO) and TNF-α inflammatory mediators in macrophages showed anti-inflammatory effects of N. sativa [36]. The methanolic extract N. sativa increases the total white blood cells (WBC) count as well as bone marrow cellularity. This immunomodulatory effect was evident by increasing the spleen weight of treated rats [37]. Volatile oil of N. sativa seeds possess cytotoxic and immunomodulating properties [38].

Dyslipidemia:

The study revealed that, hyperlipidemia patients taking 2 teaspoons of N. sativa seeds for 6 consecutive weeks, showed there is a decrease in LDL-C levels and also increases HDL-C levels [39]. The study also revealed that in both male and females daily 2 spoon of N. sativa seed for 4 weeks causes increases in the HDL-C levels and reduces the body weight [40]. It was found that in coronary artery disease daily intake of 500 mg powder of seed for 6 months with statin 10-20 mg per day, exhibit decreased in serum very low density lipoprotein (VLDL) and LDL levels and also increased HDL levels, while not decreasing VLDL and LDL levels when statin taking alone [41]. It was also found that, there is a significant reduction in the triglycerides, cholesterol, and prolactin levels in case of using N. sativa oil whereas taking of crushed seeds, there is marked increases in white blood cell (WBC) and hemoglobin percentage [42].

Antiepileptic activity:

N. sativa have antiepileptic and antioxidant activity. In a study of pentylentetrazol (PTZ) induced convulsion N. sativa oil significantly reduces the convulsion. Thus from the above study we can say that N. sativa oil having neuroprotective effect. Methanolic extract of N. sativa seed possess significant antioxidant activity [43, 44].

Gastrointestinal effects:

In a study, it was concluded that N. sativa has gastro protective effective against hepatic ischemia. In another study it was shown that N. sativa oil has an activity of increased mucin content glutathione level and decreased gastric histamine level and also producing protective effect against ethanol induced ulcer [45]. Preliminary reports suggested that N. sativa oil improved autoimmune diseases like Celiac disease (CD). It was noticed that thymoquinone having gastro protective effect. This effect may be due to poor secretion of amylase and lipase from pancreatic cells [46].

Antioxytocic and anti-fertility activity:

N. sativa seeds possess antioxytocic activity. The extract inhibiting smooth muscle contraction which proposes the anti-oxytocic efficacy of N. sativa seeds oil [47,48]. N. sativa has been shows antifertility effects in albino rats which may be attributed to its estrogenic activity [49].

Respiratory effects:

Boiled extract of N. sativa (50 and 100 mg per kg) shows brochiodilatary effects [50]. In case of tonsillopharynglities 360 mg of N. sativa and 50 mg of Phyllanthus niruri extracts along with placebo showed a marked alleviating the symptoms of acute tonsillopharynglities, which may be attributed to its immune-modulatory action and anti- inflammatory actions [51].

Antiviral activity:

Black seed oil of N. sativa was administred Intraperitoneal (i.p.) to mice. It was noticed that on day third, extract treatment decreased number and cytolytic function of NK cells. There was a significant protection of liver and spleen were found on day 10^th day of the treatment against murine cytomegalovirus. So N. sativa extract showed antiviral effect [52]. N. sativa seed and oil have both stimulating as well as suppressor characteristics of T cell. It is also observed that oil and seed extract of N. sativa having inhibitory effect on human immune deficiency virus [53].

Dermatological properties:

N. sativa plant had been used as a folk medicine. From the current investigation it is shown that, the ethanolic extract of N. sativa seed having antipsoriatic activity by using mouse tail method. The N. sativa lotion 10% also possess significantly reducing mean lesion count of papules and pustules on continuous therapy for 2 months [54]. The active principle of N. sativa, thymoquinone and the lyophilized seed extract shows significant skin darkening on isolated melanophores of the wall lizard. It mainly shows melanin dispersal effects, which is antagonized by anticholinergics like atropine, and potentiate the effect by cholinesterase inhibitors like neostigmine [55]. Another study had been carried out in eczema patient, in which there is a comparative study between Nigella and betamethasone and Eucerin ointment, which was applied for 4 weeks, twice a daily. The result shows that, N. sativa and betamethasone cause the rapid improvement of symptoms on hand eczema, with compared to Eucerin, when the severity of eczema was accessed by hand eczema severity index method [56].

Nephroprotective activity:

N. sativa oil possess Nephroprotective activity against gentamicin (GM) induced nephrotoxicity and this study revealed Nephroprotective activity of black cumin by lowering serum creatinine, blood urea nitrogen [57]. One of the study also revealed that N. sativa oil possesses kidney protection against on methotrexate-induced nephrotoxicity [58]. There was a significant decreases in total oxidant status (TOS), oxidative stress index (OSI) and elevation of total antioxidant capacity (TAC) parameters after N. sativa treatment [59].

Testicular-protective activity:

The active constituent of N. sativa i.e. thymoquinone possess testicular protective activity against methotrexate induced testicular toxicity in mice. Thymoquinone lowering total antioxidant capacity (TAC) as well as prevented the rise level of myeloperoxidase. Mice treated with methotrexate showed interstitial space dilatation, edema, severe disruption of the seminiferous epithelium and reduced diameter of the seminiferous tubules which was observed in light microscopy. One of the study revealed that thymoquinone may be helpful in drop down the destructive effects of methotrexate on testicular tissue [60].

Antidepressant activities:

N. sativa aqueous and methanol extracts showed neuropharmacological activities especially depressant action [61]. Further, administration of N. sativa for long period of time improves learning and memory of rat brain. This effect may be possible due to injection of N. sativa decreases 5-HT levels showed anxiolytic effect [62].

Anticonvulsant activity:

N. sativa aqueous extract showed anticonvulsant activity and this effect may possess due to the presence of major constituents i.e. thymoquinone, p-cymene and α-pinene. The activity was investigated against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced convulsions [63]. The active principles obtained from this plant parts possess various biological activity have been tabulated in brief (See Table.1).

Wound healing activity:

Aqueous extract of N. sativa seed ointment were prepared using polythyleneglycol and applied topically showed significant wound healing activity in both excision and incision wound healing models [64].

Table 1: Various active constituents of Negilla sativa.

Plant part	Extract	Pharmacological properties	Active constituents	References
Seed	Ethanolic	Anti-bacterial activity	Thymohydroquinone and melanin	[21]
Seed	Ethanolic, Aqueous	Anti-fungal activity	Thymoquinone	[23]
Seed	Aqueous	Anti-cancer activity	Saponins, thymoquinone and alpha-hederin	[27]
Seed	Ethanolic	Antioxidant activity	Flavonoids, alkaloids, tannins, Thymoquinone carvacrol, t-anethole and 4-terpineol	[31]
Seed	Aqueous	Anti-diabetic activity	Thymoquinone	[33]
Seed	Aqueous, Ethanolic	Anti-inflammatory activity	Thymoquinone	[35]
Seed	Aqueous	Immuno-protective activity	Alpha linoleic acid, stearic acid	[38]
Seed	Ethanolic	Gastro-protective activity	Thymoquinone	[45]
Seed	Ethanolic	Neuro-protective activity	Thymoquinone	[57, 58]

CONCLUSION:

N. sativa is an important Indian medicinal plant which has great medical potency to cure various diseases such as diarrhoea, anorexia, dyspepsia, bronchitis, asthma, inflammatory etc. Its active constituents like oleic acid, palmitic acid, linoleic acid. Aromatics contain α-thujene, thymol, α-pinene, thymoquinone, dihydrothymoquinone are the major biomarker which may be responsible for pharmacological activity. However, thymoquinone is chiefly accountable for anti-fungal, anti-bacterial, anti-inflammatory, anti-diabetic and neuroprotective activity.

CONFLICT OF INTEREST STATEMENT:

We declare that we have no conflict of interest.

ACKNOWLEDGEMENT:

The authors are grateful to Indian Council of Medical Research (ICMR), New Delhi, India (45/5/2013/ BMS/TRM) for providing financial aid in the form of fellowship.

FOUNDATION PROJECT:

The study was financially supported by Indian Council of Medical Research (ICMR), New Delhi, India (Grant No. (45/5/2013/ BMS/TRM).

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Received on 13.05.2019 Modified on 05.06.2019

Research J. Pharm. and Tech. 2019; 12(7):3111-3116.

DOI: 10.5958/0974-360X.2019.00526.2