REVIEW ARTICLE Year : 2022  |  Volume : 12  |  Issue : 12  |  Page : 495-503

Antidepressant and anti-nociceptive effects of Nigella sativa and its main constituent, thymoquinone: A literature review

Akbar Anaeigoudari
Department of Physiology, School of Medicine, Jiroft University of Medical Science, Jiroft, Iran

Date of Submission13-Oct-2022Date of Decision31-Oct-2022Date of Acceptance09-Nov-2022Date of Web Publication23-Dec-2022

Correspondence Address:
Akbar Anaeigoudari
Department of Physiology, School of Medicine, Jiroft University of Medical Science, Jiroft
Iran

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2221-1691.363875

Medicinal plants and their ingredients have beneficial effects on human health. Nigella sativa is a herbal plant with multiple biological and pharmacological activities. Previous studies demonstrated the anti-inflammatory and antioxidant properties of Nigella sativa and its main constituent thymoquinone significantly contributes to the antidepressant and anti-nociception effects of this plant. It has been reported that thymoquinone may achieve its antidepressant effect by preventing the elimination of brain neurotransmitters affecting depression such as serotonin. The role of brain-derived neurotrophic factors in the antidepressant effects of thymoquinone has also been documented. Additionally, thymoquinone can attenuate pain by upregulation of intracellular signaling pathways related to nitric oxide and K+ATP channels. The present review summarizes the antidepressant and anti-nociceptive activity of Nigella sativa and its main constituent thymoquinone by searching literature on electronic databases such as PubMed, Web of Science, Scopus, and Google Scholar from the beginning of 2010 until the end of August 2022.

Keywords: Nigella sativa; Thymoquinone; Antidepressant; Anti-nociceptive; Depression; Anti-inflammatory; Sickness behaviors; Pain

How to cite this article:
Anaeigoudari A. Antidepressant and anti-nociceptive effects of Nigella sativa and its main constituent, thymoquinone: A literature review. Asian Pac J Trop Biomed 2022;12:495-503
How to cite this URL:
Anaeigoudari A. Antidepressant and anti-nociceptive effects of Nigella sativa and its main constituent, thymoquinone: A literature review. Asian Pac J Trop Biomed [serial online] 2022 [cited 2022 Dec 23];12:495-503. Available from: https://www.apjtb.org/text.asp?2022/12/12/495/363875   1. Introduction 

In recent years, the focus on traditional medicine and use of natural products derived from medicinal plants has increased[1]. Public interest in use of herbal medicines is due to their lower side effects and availability than modern drugs[2]. Therefore, in research centers, a large number of scientific studies are conducted to discover the effective substances of medicinal plants and their therapeutic properties[3],[4].

Nigella sativa (N. sativa), black cumin or black seed, is an annual flowering plant belonging to Ranunculaceae family. This herbaceous plant grows in different regions of Asia, Africa, and Europe, and possesses threadlike leaves and delicate flowers. The colors of flowers can be white, yellow, pale blue, and pink. The fruit of N. sativa is a large and inflated capsule made of three to seven united follicles containing black seeds which are utilized as a spice[2],[5].

Because of various biological and pharmacological activities, N. sativa is known as a miracle herb[6]. Its biological activities include anti-inflammatory[7], antioxidant[8] antimicrobial[9], anti- apoptotic[10], anti-mutagenic[11] and anti-cancer[12] activities. N. sativa has been known to be a good remedy for alleviation of chronic obstructive pulmonary diseases[13], cough[14], fever[15], diarrhea[16], and eczema[17]. It is also traditionally employed to cure increased level of blood glucose[18], high blood pressure[19], allergic reactions[20], and stomach ache[2]. Thymoquinone (TQ) presented in the extract of N. sativa contributes to the majority of these effects. This review will summarize the reported activities of this plant and its main constituent TQ on depression and pain.

  2. Method 

Scientific evidence cited in this review was collected from electronic databases such as PubMed, Web of Science, Scopus, and Google Scholar from the beginning of 2010 until the end of August 2022 using keywords such as “Nigella sativa” or “thymoquinone” and “antidepressant”, “sickness behaviors”, “anti-nociceptive” and “pain” [Figure 1]. Human and animal studies were checked.

  3. Chemical compounds of N. sativa 

Biochemical analyses proved the presence of various types of chemical compounds in N. sativa. An important group of these compounds is volatile phytochemicals in the essential oil of N. sativa including TQ, thymol, dithymoquinone, carvacrol, 4-terpineol, p-cymene, α-pinene, β-pinene and t-anethole[21]. Among these compounds, TQ has different pharmacological properties. Other chemicals found in N. sativa extract are alkaloids such as nigellicimine, nigellicimine-N-oxide, nigellicine, and nigellidine. In addition, the essential oil of N. sativa contained proteins, saturated and unsaturated free fatty acids, vitamins, and minerals[22].

  4. N. sativa and traditional medicine 

In traditional medicine, N. sativa has been demonstrated to have considerable therapeutic effects on different kinds of ailments and disturbances. In this section, some of the applications of N. sativa and its active ingredient TQ in traditional medicine will be mentioned.

In a study by Abd-Elkareem et al., N. sativa seeds showed the renoprotective effect against monosodium glutamate-induced nephrotoxicity via ameliorating the oxidative stress status and increasing the level of antioxidant agents such as superoxide dismutase (SOD) and glutathione[23]. In a similar study, it was proved that the hepatoprotective effect of N. sativa in a rat model of monosodium glutamate-caused hepatotoxicity was attributed to its antioxidant and anti-apoptotic properties[24]. Based on the research carried out by Liang et al., TQ derived from N. sativa also protected the human skin keratinocytes from ultraviolet irradiation-induced injuries by suppressing inflammatory reactions and neutralization of free radicals[25]. It has been documented that a novel polyherbal formulation containing TQ dose-dependently improved the hepatorenal dysfunction caused by CCl4[26]. The role of N. sativa in the treatment of cardiovascular diseases[27], type 2 diabetes mellitus[28], rheumatoid arthritis[29], and asthma[30] has also been documented. In an animal model of lipopolysaccharide (LPS)-induced memory impairment, hydro-alcoholic extract of N. sativa corrected the performance of rats in Morris water maze and passive avoidance tests by ameliorating the brain inflammation and oxidative stress[31]. Asiaei et al. also showed that N. sativa could exert a neuroprotective effect on hypothyroidism-induced injuries in the hippocampal tissue of juvenile rats[32]. Additionally, TQ has been recognized to have a potent ability in reversing the detrimental effects of propylthiouracil on cognitive activities and brain oxidative damage in juvenile rats[33]. In patients with Hashimoto’s thyroiditis, N. sativa attenuated the severity of disease, decremented the level of thyroid stimulating hormone, anti-thyroid peroxidase antibodies, and vascular endothelial growth factor-1 and increased the serum concentration of triiodothyronine[34]. Previous studies also reported the antimicrobial properties of N. sativa extract. For example, in a study conducted by Tiji et al., the antifungal and antibacterial effect of N. sativa extracts against Candida albicans, Staphylococcus aureus, Bacillus cereus, and Escherichia coli was confirmed. They reported that TQ, beta-cymene, alpha-thujene, origanene, cysteine, gallic acid, and apigenin compounds play main roles in the antimicrobial effects of N. sativa[35]. Furthermore, N. sativa and its constituents showed useful effects against infections resulting from coronavirus disease 2019 (COVID-19)[36]. TQ has also been recognized to have anti-microsporidial effect against Encephalitozoon intestinalis in vitro[37].

  5. Anti-depressant effects of N. sativa and TQ 

Depression is a mental disorder that is characterized by confusion[38], sadness[39], anxiety[40], and lack of interest and motivation[41]. Epidemiologic studies show that a large number of people suffer from depression and it has become a human health problem[42]. Genetic and environmental factors such as stress are considered the main causes of the development of depression[43]. Depression may affect the structure and function of different areas of the brain. It has been indicated that depression can lead to hippocampus and prefrontal cortex atrophy[44]. In addition, previous studies show that synaptic plasticity impairment in some brain areas including the hippocampus can play a key role in the pathogenesis of depression[45]. Neurotrophic factors are endogenous soluble proteins regulating neuronal plasticity[46]. One of the most well-known neurotrophic factors is brain-derived neurotrophic factor (BDNF). It has been illustrated that stress inhibits the generation of BDNF in the hippocampus[47]. Treatment by medicinal plants can mitigate the complications of depression by affecting BDNF production[48]. In a clinical trial, researchers evaluated the effect of the capsules containing 1000 mg of N. sativa oil extract on male depressed patients. The results demonstrated that N. sativa extracts resulted in a remarkable reduction in depression score, anxiety, and stress and significantly enhanced the serum level of BDNF[49]. It has been also reported that a significant number of dialysis patients suffer from different degrees of depression and suicide is prevalent among them[50]. In a double-blind, randomized controlled trial, the effect of N. sativa oil supplementation on hemodialysis-induced depression was checked. In this research, treatment with two soft gels of N. sativa attenuated the symptoms of depression in patients[51].

Sickness behaviors are behavioral complexes that may be induced by infections, immune system disturbances, and overproduction of pro-inflammatory cytokines[52]. There are noticeable similarities between sickness behaviors and depression. Anorexia, weight loss, sleepiness, fatigue, malaise, anxiety, and cognitive deficits are considered common points between sickness behaviors and depression[53]. In animal studies, sickness behaviors were assessed by behavioral techniques including open field, elevated plus maze, and forced swimming tests[54]. It has been documented that acute administration of 100, 200, and 400 mg/kg of ethanolic extract of N. sativa exhibited marked anti-anxiety and antidepressant effects in the open field, elevated plus maze, and forced swimming tests[55]. Microbial toxins can disturb immune system function and induce anxiety and depression-like behaviors. LPS is a potent bacterial endotoxin that stimulates the production of pro-inflammatory cytokines and consequently induces sickness behaviors[56]. In an animal study, pretreatment with hydro-alcoholic extract of N. sativa (100, 200, and 400 mg/kg) could improve LPS-induced sickness behaviors in rats, which was attributed to anti-inflammatory and antioxidant effects of N. sativa[57]

Increasing evidence reveals that toxic heavy metals can induce depression-like behaviors[58]. Mercury is a toxic heavy metal that can hazard the stomach, kidneys, and cardiovascular system[59]. The effects of N. sativa oil (2 mL/kg/day) against mercuric chloride-induced anxiety and depression were evaluated in Wistar rats. In this study, administration of mercuric chloride for three weeks induced anxiety and depression-like behaviors in rats. Treatment with 2 mL/kg of N. sativa oil for four weeks reversed the harmful effects of mercuric chloride on behavioral functions of rats, as evidenced by increasing the number of line crossing, time spent in open arm, and swimming time in the forced swimming test. The improvement in behavioral performance was linked to antioxidant effect of N. sativa oil[60].

TQ derived from N. sativa is well known for its antioxidant and anti-inflammatory properties[61]. Besides free radicals scavenging effect, TQ possesses the antimicrobial[62], anti-toxicity[63], anti-diabetic[64], antihypertensive[65] and hepatoprotective[66] properties. One of the limitations of use of TQ in scientific studies is low solubility and bioavailability. To overcome this problem, a formulation of TQ solid lipid nanoparticles (TQSLN) is used[67]. Serotonin (5-HT) is a monoamine neurotransmitter with antidepressant effects which is synthesized from amino acid tryptophan (TRP)[68]. In addition, TRP can be metabolized through the kynurenine (KYN) pathway[69]. Indoleamine-2,3-dioxygenase (IDO) as the first enzyme of this pathway is activated by inflammatory mediators such as interferon-gamma (IFN-γ). Therefore, the activity of IDO is associated with the decrement of 5HT level and the enhancement of KYN concentration[70]. KYN pathway has also been exhibited to have a key role in depression[69]. Alam et al. investigated the antidepressant effect of TQSLN (20 mg/kg, p.o.) in a rat model of chronic forced-swim stress. In this study, the antidepressant effect of TQSLN was associated with decreased concentration of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and increased levels of BDNF in the hippocampus tissue of rats. The results of the study also demonstrated that treatment with TQSLN reversed the increased activity of IDO in stressed rats. Reduction of IDO activity was determined by a reduced ratio of hippocampal KYN/TRP and an increased ratio of 5HT/TRP[71]. Based on the results of another study, TQSLN alleviated depressive behavioral conditions in LPS-exposed rats. TQSLN significantly decreased the immobility time in the tail suspension test. In the forced swimming test, TQSLN lessened the immobility time and increased swimming time and climbing time in rats. The improvement of behavior performance was associated with a significant increase in BDNF and 5HT/TRP ratio and a considerable reduction in KYN/TRP ratio and the expression of TNF-α, IL-6, and NF-κB in hippocampus tissue of rats treated by TQSLN[72].

It has also been documented that some antihypertensive drugs such as reserpine are depressogenic[73]. In another study, Samad et al. showed that 10 and 20 mg/kg of TQ improved reserpine-stimulated anxiety and depression in mice by reducing inflammation and oxidative damage of the hippocampus[74].

Diabetes mellitus is a metabolic disorder that threatens the health of a large number of people throughout the world[5]. There is a two-way relationship between diabetes mellitus and depression[75]. In an animal study, TQ (10 and 20 mg/kg) could mitigate depression in type 2 diabetic rats by decreasing the level of IL-1β and TNF-α and oxidative stress[76].

Concanavalin A (Con A) is a plant mitogen belonging to legume lectin family which strongly stimulates the immune system[77]. This chemical compound has also been reported to trigger sickness behaviors in rodents[78]. Nazir et al. reported that TQ (10 mg/kg) could protect the mice against Con A-caused anxiety and depression via the anti-inflammatory activity[79]. In addition, the anxiolytic effect of TQ (2.5 and 5 mg/kg/day) against arsenic-caused hippocampal damage in rats was examined. Firdaus et al. revealed that pretreatment with 5 mg/kg of TQ improved the behavior performance in behavior tests, enhanced glutathione and SOD activity and mitigated the levels of lipid peroxidation (LPO), TNF-α and IFN-γ in hippocampus tissue of rats[80]. [Table 1] exhibits the antidepressant effects of N. sativa and TQ.

Table 1: Antidepressant effects of Nigella sativa and its main constituent thymoquinone.

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  6. Anti-nociceptive effects of N. sativa and TQ 

Besides unpleasant feelings, pain is a sensory modality providing human survival. Few people in the world do not complain of pain[81]. Nociceptors are free nerve endings that detect different types of noxious stimuli. Two types of nerve fibers send pain impulses to the brain: (1) C fibers and (2) Aδ fibers. C fibers are small in diameter and unmyelinated. They send the nerve impulses slowly. Aδ fibers are large in diameter, myelinated, and conduct pain impulses faster[82],[83]. Pain sensations can be irritated due to inflammation and tissue injuries[84]. Chemical substances such as potassium[85], bradykinin[86], histamine[87], serotonin[88], substance P[89] and prostaglandins[90] can stimulate nociceptors. Endogenous chemicals including enkephalins, endorphins, and dynorphin also relieve pain by binding to the opioid receptors[91]. In addition, some drugs[92] and natural compounds[93] have been reported to mitigate pain. Dysmenorrhea, also named painful cramps, begins one or two days before menstruation[94]. This pain can result in vomiting, fatigue, and nausea[95]. Drug and non-drug treatments are recommended as the main methods for relieving dysmenorrhea. Herbal medicines including curcumin[96], saffron[97], and thyme[98] have been employed for alleviating dysmenorrhea. In a randomized double-blind clinical trial, N. sativa oil exerted analgesic effects in female students suffering from primary dysmenorrhea[99]. In another study, a 5% gel of N. sativa was used for reducing the worst experimental pain in patients with breast cancer who were treated by radiotherapy. In this study, a visual analog scale evaluated the worst experimental pain and the findings indicated that the mean score of pain in patients exposed to 5% gel was significantly lower than those treated with a placebo[100]. Kooshki et al. also reported the soothing effect of N. sativa oil (1 mL every 8 h for 3 weeks) on osteoarthritis-induced knee pain in elderly men and women[101]. In a rat model of arthritis, oral administration of 1.82 mL/kg and 0.91 mL/kg of N. sativa oil also exerted anti-nociceptive and anti-inflammatory effects[102]. Panch phoron comprises five plant species containing N. sativa, Foeniculum vulgare, Trigonella foenum-graecum Linn, Brassica nigra, and Cuminum cyminum[103]. This mixture was used in traditional medicine and has different therapeutic effects. Gias et al. demonstrated the anti-nociceptive effect of panch phoron extracts (100, 300, and 500 mg/kg) in the writhing test. Based on the results, the extract dose-dependently attenuated pain and inflammation in mice[104]. In addition, Zakaria et al. investigated the analgesic effect of 0.5 mL of N. sativa extract in a mice model of acetic acid-caused writhing. Their findings revealed that the extract could significantly lower the number of writhing compared with the control group, the analgesic effect of which was comparable to that of aspirin[105]. It has also been reported that intraperitoneal administration of 50 mg/kg of ethanolic N. sativa seed extract reduced the number of writhing compared to the control group in experimentally stimulated pain in albino mice[106].

Neuropathic pain is a chronic annoying condition that is excited by damage to neuronal fibers in the peripheral and central nervous system. It can be associated with hyperalgesia caused by noxious stimuli or may be evoked by non-painful stimuli (allodynia)[107]. Due to the lack of proper effect of available drugs on neuropathic pain, recent studies are conducted to discover natural remedies attenuating this chronic condition. According to current scientific evidence, oxidative stress has a high contribution to induction of neuropathic pain[108]. Amin et al. examined the effect of TQ (1.25, 2.5, and 5 mg/kg) on pain irritated by chronic constriction injury in the sciatic nerve of rats. The results confirmed the improving effect of TQ on neuropathic pain by enhancing the antioxidant ability[109].

The role of signaling pathways related to nitric oxide (NO) in modulation of pain perception has been confirmed in many studies. It has been demonstrated that the activation of L-arginine, NO, 3’,5’-cyclic guanosine monophosphate (cGMP) and potassium (K+) channels (L-arginine/NO/cGMP/KATP) pathway can result in the mitigation of pain[110],[111]. In an experimental research, the effect of peripheral (10, 20, and 40 µg/paw) and central (2, 4, and 8 µg/kg) administration of TQ on formalin-induced pain in rats was evaluated. Ipsilateral peripheral injection of 20 and 40 µg TQ into the paw of rats and intracerebroventricular (ICV) administration of TQ remarkably decreased the paw licking time in the early and late phases of the formalin test. In this study, intraperitoneal injection of 100 µg/ paw of L-NG-nitroarginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, reversed the anti-nociceptive effect of 20 µg/paw of TQ in the late phase of the formalin test. ICV injection of 1 µg/kg of L-NAME also attenuated the effect of 8 µg/kg of TQ in both phases of the formalin test. To determine the role of cGMP in the anti-nociceptive effect of TQ, methylene blue as a guanylyl cyclase inhibitor was employed. It could antagonize the positive effect of TQ (20 µg/paw, i.p. and 8 µg/kg, ICV) on formalin-induced pain. The blocker of the voltage-gated K+ATP channel, glibenclamide, was also used for checking the role of K+ ions in the anti-nociceptive effects of TQ. The results illustrated that glibenclamide could diminish the peripheral and central anti-nociceptive effect of TQ[112]. [Table 2] summarizes the anti-nociceptive effects of N. sativa and TQ.

  7. Conclusion 

The clinical and experimental evidence exhibts that N. sativa exerts alleviative effects on depression symtoms and pain. In addition, TQ as a main effective ingredient of N. sativa has good therapeutic effects on sickness behaviors and pain. Antidepressant and analgesic effects of N. sativa and TQ can be arrtibuted to their antioxidant and anti-iflammatory properties. One of underlying mechanisms of antidepressant effects of TQ is enhancement of brain level of serotonin and upregulation of BDNF. Upregulation of L-arginine/NO/cGMP/KATP channel pathway also involves in the anti-nociceptive effect of TQ. Although the results of many studies confirm antidepressant and anti-nociceptive effects of N. sativa and TQ, complementary studies in this field are required to further elucidate the mechanisms of their anti-nociceptive action.

Conflict of interest statement

The author declares that there is no conflict of interest.

Funding

The author received no extramural funding for the study.

 

  References 
1.Cheng X, Hu J, Liu X, Tibenda JJ, Wang X, Zhao Q. Therapeutic targets by traditional Chinese medicine for ischemia-reperfusion injury induced apoptosis on cardiovascular and cerebrovascular diseases. Front Pharmacol 2022; 13: 934256.  
    2.Dalli M, Bekkouch O, Azizi SE, Azghar A, Gseyra N, Kim B. Nigella sativa L. phytochemistry and pharmacological activities: A review (2019-2021). Biomolecules 2021; 12(1): 1-37.  
    3.Shirmard LR, Shabani M, Moghadam AA, Zamani N, Ghanbari H, Salimi A. Protective effect of curcumin, chrysin and thymoquinone injection on trastuzumab-induced cardiotoxicity via mitochondrial protection. Cardiovasc Toxicol 2022; 22(7): 663-675.  
    4.Zhang L, Zhang H, Ma J, Wang Y, Pei Z, Ding H. Effects of thymoquinone against angiotensin II-induced cardiac damage in apolipoprotein E-deficient mice. Int J Mol Med 2022; 49(5): 1-12.  
    5.Anaeigoudari A, Safari H, Khazdair MR. Effects of Nigella sativa, Camellia sinensis, and Allium sativum as food additive on metabolic disorders, a literature review. Front Pharmacol 2021; 12: 3155.  
    6.Islam MN, Hossain KS, Sarker PP, Ferdous J, Hannan MA, Rahman MM, et al. Revisiting pharmacological potentials of Nigella sativa seed: A promising option for COVID-19 prevention and cure. Phytother Res 2021; 35(3): 1329-1344.  
    7.Fatima Shad K, Soubra W, Cordato DJ. The role of thymoquinone, a major constituent of Nigella sativa, in the treatment of inflammatory and infectious diseases. Clin Exp Pharmacol Physiol 2021; 48(11): 1445-1453.  
    8.Butt AS, Nisar N, Mughal TA, Ghani N, Altaf I. Anti-oxidative and anti-proliferative activities of extracted phytochemical compound thymoquinone. J Pak Med Assoc 2019; 69(10): 1479-1485.  
    9.Khazdair MR, Ghafari S, Sadeghi M. Possible therapeutic effects of Nigella sativa and its thymoquinone on COVID-19. Pharm Biol 2021; 59(1): 694-701.  
    10.Erboga M, Kanter M, Aktas C, Sener U, Fidanol Erboga Z, Bozdemir Donmez Y, et al. Thymoquinone ameliorates cadmium-induced nephrotoxicity, apoptosis, and oxidative stress in rats is based on its anti-apoptotic and anti-oxidant properties. Biol Trace Elem Res 2016; 170(1): 165-172.  
    11.Helvacioğlu S, Charehsaz M, Güzelmeriç E, Oçkun MA, Ayran İ, Kirmizibekmez H, et al. Protective effect of Nigella sativa and Nigella damascena fixed oils against aflatoxin induced mutagenicity in the classical and modified ames test. Chem Biodivers 2021; 18(10). doi: 10.1002/cbdv.202000936.  
    12.Majdalawieh AF, Fayyad MW. Recent advances on the anti-cancer properties of Nigella sativa, a widely used food additive. J Ayurveda Integr Med 2016; 7(3): 173-180.  
    13.Al-Azzawi MA, AboZaid MM, Ibrahem RAL, Sakr MA. Therapeutic effects of black seed oil supplementation on chronic obstructive pulmonary disease patients: A randomized controlled double blind clinical trial. Heliyon 2020; 6(8). doi: 10.1016/j.heliyon.2020.e04711.  
    14.Mortazavi Moghaddam SG, Kianmehr M, Khazdair MR. The possible therapeutic effects of some medicinal plants for chronic cough in children. Evid Based Complement Alternat Med 2020. doi: 10.1155/2020/2149328.  
    15.Forouzanfar F, Bazzaz BSF, Hosseinzadeh H. Black cumin (Nigella sativa) and its constituent (thymoquinone): A review on antimicrobial effects. Iran J Basic Med Sci 2014; 17(12): 929.  
    16.Hashem-Dabaghian F, Agah S, Taghavi-Shirazi M, Ghobadi A. Combination of Nigella sativa and honey in eradication of gastric Helicobacter pylori infection. Iran Red Crescent Med J 2016; 18(11). doi: 10.5812/ircmj.23771.  
    17.Yousefi M, Barikbin B, Kamalinejad M, Abolhasani E, Ebadi A, Younespour S, et al. Comparison of therapeutic effect of topical Nigella with Betamethasone and Eucerin in hand eczema. J Eur Acad Dermatol Venereol 2013; 27(12): 1498-1504.  
    18.Hadi V, Pahlavani N, Malekahmadi M, Nattagh-Eshtivani E, Navashenaq JG, Hadi S, et al. Nigella sativa in controlling type 2 diabetes, cardiovascular, and rheumatoid arthritis diseases: Molecular aspects. J Res Med Scip 2021; 26: 1-14.  
    19.Alam MA, Bin Jardan YA, Raish M, Al-Mohizea AM, Ahad A, Al-Jenoobi FI. Effect of Nigella sativa and fenugreek on the pharmacokinetics and pharmacodynamics of amlodipine in hypertensive rats. Curr Drug Metab 2020; 21(4): 318-325.  
    20.Boskabady M, Mohsenpoor N, Takaloo L. Antiasthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomedicine 2010; 17(10): 707-713.  
    21.Kabir Y, Akasaka-Hashimoto Y, Kubota K, Komai M. Volatile compounds of black cumin (Nigella sativa L.) seeds cultivated in Bangladesh and India. Heliyon 2020; 6(10). doi: 10.1016/j.heliyon.2020. e05343.  
    22.Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddique NA, et al. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed 2013; 3(5): 337-352.  
    23.Abd-Elkareem M, Soliman M, Abd El-Rahman MA, Abou Khalil NS. Effect of Nigella sativa L. seed on the kidney of monosodium glutamate challenged rats. Front Pharmacol 2022; 13. doi: 10.3389/fphar.2022.789988.  
    24.Abd-Elkareem M, Soliman M, Abd El-Rahman MA, Abou Khalil NS. The protective effect of Nigella sativa seeds against monosodium glutamate-induced hepatic dysfunction in rats. Toxicol Rep 2022; 9: 147-153.  
    25.Liang J, Lian L, Wang X, Li L. Thymoquinone, extract from Nigella sativa seeds, protects human skin keratinocytes against UVA-irradiated oxidative stress, inflammation and mitochondrial dysfunction. Mol Immunol 2021; 135: 21-27.  
    26.Ahmad A, Abuzinadah MF, Alkreathy HM, Kutbi HI, Shaik NA, Varish Ahmad V, et al. A novel polyherbal formulation containing thymoquinone attenuates carbon tetrachloride-induced hepatorenal injury in a rat model. Asian Pac J Trop Biomed 2020; 10(4): 147-155.  
    27.Razmpoosh E, Safi S, Nadjarzadeh A, Fallahzadeh H, Abdollahi N, Mazaheri M, et al. The effect of Nigella sativa supplementation on cardiovascular risk factors in obese and overweight women: A crossover, double-blind, placebo-controlled randomized clinical trial. Eur J Nutr 2021; 60(4): 1863-1874.  
    28.Lak YS, Khorram S, Abbasi MM, Asghari-Jafarabadi M, Tarighat-Esfanjani A, Bazri E, et al. The effects of natural nano-sized clinoptilolite and Nigella sativa supplementation on serum bone markers in diabetic rats. Bioimpacts 2019; 9(3): 173-178.  
    29.Kheirouri S, Hadi V, Alizadeh M. Immunomodulatory effect of Nigella sativa oil on T lymphocytes in patients with rheumatoid arthritis. Immunol Invest 2016; 45(4): 271-283.  
    30.Ikhsan M, Hiedayati N, Maeyama K, Nurwidya F. Nigella sativa as an anti-inflammatory agent in asthma. BMC Res Notes 2018; 11(1): 1-5.  
    31.Norouzi F, Hosseini M, Abareshi A, Beheshti F, Khazaei M, Shafei MN, et al. Memory enhancing effect of Nigella Sativa hydro-alcoholic extract on lipopolysaccharide-induced memory impairment in rats. Drug Chem Toxicol 2019; 42(3): 270-279.  
    32.Asiaei F, Fazel A, Rajabzadeh AA, Hosseini M, Beheshti F, Seghatoleslam M. Neuroprotective effects of Nigella sativa extract upon the hippocampus in PTU-induced hypothyroidism juvenile rats: A stereological study. Metab Brain Dis 2017; 32(5): 1755-1765.  
    33.Baghcheghi Y, Hosseini M, Beheshti F, Salmani H, Anaeigoudari A. Thymoquinone reverses learning and memory impairments and brain tissue oxidative damage in hypothyroid juvenile rats. Arq Neuropsiquiatr 2018; 76: 32-40.  
    34.Farhangi MA, Dehghan P, Tajmiri S, Abbasi MM. The effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF)-1, Nesfatin-1 and anthropometric features in patients with Hashimoto’s thyroiditis: A randomized controlled trial. BMC Complement Altern Med 2016; 16(1): 1-9.  
    35.Tiji S, Rokni Y, Benayad O, Laaraj N, Asehraou A, Mimouni M. Chemical composition related to antimicrobial activity of Moroccan Nigella sativa L. extracts and isolated fractions. Evid Based Complement Alternat Med 2021. doi: 10.1155/2021/8308050.  
    36.Koshak AE, Koshak EA, Mobeireek AF, Badawi MA, Wali SO, Malibary HM, et al. Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial. Complement Ther Med 2021; 61. doi: 10.1016/j.ctim.2021.102769.  
    37.Çetinkaya U, Sezer G, Charyyeva A. Anti-microsporidial effect of thymoquinone on Encephalitozoon intestinalis infection in vitro. Asian Pac J Trop Biomed 2020; 10(1): 42-46.  
    38.Lai S, Zhong S, Wang Y, Zhang Y, Xue Y, Zhao H, et al. The prevalence and characteristics of MCCB cognitive impairment in unmedicated patients with bipolar II depression and major depressive disorder. J Affect Disord 2022; 310: 369-376.  
    39.Lu X, Shi D, Liu Y, Yuan J. Speech depression recognition based on attentional residual network. Front Biosci 2021; 26(12): 1746-1759.  
    40.Nguyen M, Reyes H, Pence B, Muessig K, Hutton H, Latkin C, et al. Effects of two alcohol reduction interventions on depression and anxiety symptoms of ART clients in Vietnam. AIDS Behav 2022; 26(6): 1829-1840.  
    41.Grahek I, Shenhav A, Musslick S, Krebs RM, Koster EH. Motivation and cognitive control in depression. Neurosci Biobehav Rev 2019; 102: 371-381.  
    42.Sarokhani D, Parvareh M, Dehkordi AH, Sayehmiri K, Moghimbeigi A. Prevalence of depression among iranian elderly: Systematic review and meta-analysis. Iran J Psychiatry 2018; 13(1): 55.  
    43.Wankerl M, Miller R, Kirschbaum C, Hennig J, Stalder T, Alexander N. Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles. Transl Psychiatry 2014; 4(6): e402.  
    44.Duman RS, Deyama S, Fogaça MV. Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci 2021; 53(1): 126-139.  
    45.Liu D, Lv F, Min S, Yang Y, Chen L. Inhibition of NLRP3 inflammasome-mediated neuroinflammation alleviates electroconvulsive shock-induced memory impairment via regulation of hippocampal synaptic plasticity in depressive rats. Behav Brain Res 2022; 428. doi: 10.1016/j.bbr.2022.113879.  
    46.Keifer J. Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease. J Neurosci Res 2022; 100(4): 979-991.  
    47.Phillips C. Brain-derived neurotrophic factor, depression, and physical activity: Making the neuroplastic connection. Neural Plast 2017; 2017. doi: 10.1155/2017/7260130.  
    48.Liu HT, Lin YN, Tsai MC, Wu YC, Lee MC. Baicalein exerts therapeutic effects against endotoxin-induced depression-like behavior in mice by decreasing inflammatory cytokines and increasing brain-derived neurotrophic factor levels. Antioxidants 2022; 11(5): 947.  
    49.Zadeh AR, Eghbal AF, Mirghazanfari SM, Ghasemzadeh MR, Nassireslami E, Donyavi V. Nigella sativa extract in the treatment of depression and serum brain-derived neurotrophic factor (BDNF) levels. J Res Med Sci 2022; 27: 28. doi: 10.4103/jrms.jrms_823_21.  
    50.Hosseini SH, Espahbodi F, Goudarzi SMMM. Citalopram versus psychological training for depression and anxiety symptoms in hemodialysis patients. Iran J Kidney Dis 2012; 6(6): 446-451.  
    51.Rahmani A, Maleki V, Niknafs B, Tavakoli-Rouzbehani OM, Tarighat-Esfanjani A. Effect of Nigella sativa supplementation on kidney function, glycemic control, oxidative stress, inflammation, quality of life, and depression in diabetic hemodialysis patients: Study protocol for a double-blind, randomized controlled trial. Trials 2022; 23(1): 1-9.  
    52.Krapić M, Kavazović I, Wensveen FM. Immunological mechanisms of sickness behavior in viral infection. Viruses 2021; 13(11): 2245.