|Year : 2022 | Volume
| Issue : 12 | Page : 495-503
Antidepressant and anti-nociceptive effects of Nigella sativa and its main constituent, thymoquinone: A literature review
Department of Physiology, School of Medicine, Jiroft University of Medical Science, Jiroft, Iran
|Date of Submission||13-Oct-2022|
|Date of Decision||31-Oct-2022|
|Date of Acceptance||09-Nov-2022|
|Date of Web Publication||23-Dec-2022|
Department of Physiology, School of Medicine, Jiroft University of Medical Science, Jiroft
Source of Support: None, Conflict of Interest: None
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 2023 Jun 4];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. Public interest in use of herbal medicines is due to their lower side effects and availability than modern drugs. Therefore, in research centers, a large number of scientific studies are conducted to discover the effective substances of medicinal plants and their therapeutic properties,.
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,.
Because of various biological and pharmacological activities, N. sativa is known as a miracle herb. Its biological activities include anti-inflammatory, antioxidant antimicrobial, anti- apoptotic, anti-mutagenic and anti-cancer activities. N. sativa has been known to be a good remedy for alleviation of chronic obstructive pulmonary diseases, cough, fever, diarrhea, and eczema. It is also traditionally employed to cure increased level of blood glucose, high blood pressure, allergic reactions, and stomach ache. 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. 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.
| 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. 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. 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. It has been documented that a novel polyherbal formulation containing TQ dose-dependently improved the hepatorenal dysfunction caused by CCl4. The role of N. sativa in the treatment of cardiovascular diseases, type 2 diabetes mellitus, rheumatoid arthritis, and asthma 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. Asiaei et al. also showed that N. sativa could exert a neuroprotective effect on hypothyroidism-induced injuries in the hippocampal tissue of juvenile rats. 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. 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. 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. Furthermore, N. sativa and its constituents showed useful effects against infections resulting from coronavirus disease 2019 (COVID-19). TQ has also been recognized to have anti-microsporidial effect against Encephalitozoon intestinalis in vitro.
| 5. Anti-depressant effects of N. sativa and TQ|| |
Depression is a mental disorder that is characterized by confusion, sadness, anxiety, and lack of interest and motivation. Epidemiologic studies show that a large number of people suffer from depression and it has become a human health problem. Genetic and environmental factors such as stress are considered the main causes of the development of depression. 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. 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. Neurotrophic factors are endogenous soluble proteins regulating neuronal plasticity. 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. Treatment by medicinal plants can mitigate the complications of depression by affecting BDNF production. 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. It has been also reported that a significant number of dialysis patients suffer from different degrees of depression and suicide is prevalent among them. 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.
Sickness behaviors are behavioral complexes that may be induced by infections, immune system disturbances, and overproduction of pro-inflammatory cytokines. 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. In animal studies, sickness behaviors were assessed by behavioral techniques including open field, elevated plus maze, and forced swimming tests. 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. 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. 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
Increasing evidence reveals that toxic heavy metals can induce depression-like behaviors. Mercury is a toxic heavy metal that can hazard the stomach, kidneys, and cardiovascular system. 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.
TQ derived from N. sativa is well known for its antioxidant and anti-inflammatory properties. Besides free radicals scavenging effect, TQ possesses the antimicrobial, anti-toxicity, anti-diabetic, antihypertensive and hepatoprotective 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. Serotonin (5-HT) is a monoamine neurotransmitter with antidepressant effects which is synthesized from amino acid tryptophan (TRP). In addition, TRP can be metabolized through the kynurenine (KYN) pathway. 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. KYN pathway has also been exhibited to have a key role in depression. 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. 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.
It has also been documented that some antihypertensive drugs such as reserpine are depressogenic. 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.
Diabetes mellitus is a metabolic disorder that threatens the health of a large number of people throughout the world. There is a two-way relationship between diabetes mellitus and depression. 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.
Concanavalin A (Con A) is a plant mitogen belonging to legume lectin family which strongly stimulates the immune system. This chemical compound has also been reported to trigger sickness behaviors in rodents. 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. 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. [Table 1] exhibits the antidepressant effects of N. sativa and TQ.
|Table 1: Antidepressant effects of Nigella sativa and its main constituent thymoquinone.|
Click here to view
| 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. 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,. Pain sensations can be irritated due to inflammation and tissue injuries. Chemical substances such as potassium, bradykinin, histamine, serotonin, substance P and prostaglandins can stimulate nociceptors. Endogenous chemicals including enkephalins, endorphins, and dynorphin also relieve pain by binding to the opioid receptors. In addition, some drugs and natural compounds have been reported to mitigate pain. Dysmenorrhea, also named painful cramps, begins one or two days before menstruation. This pain can result in vomiting, fatigue, and nausea. Drug and non-drug treatments are recommended as the main methods for relieving dysmenorrhea. Herbal medicines including curcumin, saffron, and thyme 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. 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. 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. 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. Panch phoron comprises five plant species containing N. sativa, Foeniculum vulgare, Trigonella foenum-graecum Linn, Brassica nigra, and Cuminum cyminum. 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. 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. 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.
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). 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. 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.
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,. 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. [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.
The author received no extramural funding for the study.
| References|| |
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
Dalli M, Bekkouch O, Azizi SE, Azghar A, Gseyra N, Kim B. Nigella sativa
L. phytochemistry and pharmacological activities: A review (2019-2021). Biomolecules
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
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
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
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
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
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
Khazdair MR, Ghafari S, Sadeghi M. Possible therapeutic effects of Nigella sativa
and its thymoquinone on COVID-19. Pharm Biol
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
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
(10). doi: 10.1002/cbdv.202000936.
Majdalawieh AF, Fayyad MW. Recent advances on the anti-cancer properties of Nigella sativa,
a widely used food additive. J Ayurveda Integr Med
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
(8). doi: 10.1016/j.heliyon.2020.e04711.
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.
Forouzanfar F, Bazzaz BSF, Hosseinzadeh H. Black cumin (Nigella sativa
) and its constituent (thymoquinone): A review on antimicrobial effects. Iran J Basic Med Sci
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
(11). doi: 10.5812/ircmj.23771.
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
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
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
Boskabady M, Mohsenpoor N, Takaloo L. Antiasthmatic effect of Nigella sativa
in airways of asthmatic patients. Phytomedicine
Kabir Y, Akasaka-Hashimoto Y, Kubota K, Komai M. Volatile compounds of black cumin (Nigella sativa
L.) seeds cultivated in Bangladesh and India. Heliyon
(10). doi: 10.1016/j.heliyon.2020. e05343.
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
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
. doi: 10.3389/fphar.2022.789988.
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
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
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
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
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
Kheirouri S, Hadi V, Alizadeh M. Immunomodulatory effect of Nigella sativa
oil on T lymphocytes in patients with rheumatoid arthritis. Immunol Invest
Ikhsan M, Hiedayati N, Maeyama K, Nurwidya F. Nigella sativa
as an anti-inflammatory agent in asthma. BMC Res Notes
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
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
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
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
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.
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
. doi: 10.1016/j.ctim.2021.102769.
Çetinkaya U, Sezer G, Charyyeva A. Anti-microsporidial effect of thymoquinone on Encephalitozoon intestinalis
infection in vitro. Asian Pac J Trop Biomed
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
Lu X, Shi D, Liu Y, Yuan J. Speech depression recognition based on attentional residual network. Front Biosci
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
Grahek I, Shenhav A, Musslick S, Krebs RM, Koster EH. Motivation and cognitive control in depression. Neurosci Biobehav Rev
Sarokhani D, Parvareh M, Dehkordi AH, Sayehmiri K, Moghimbeigi A. Prevalence of depression among iranian elderly: Systematic review and meta-analysis. Iran J Psychiatry
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
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
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
. doi: 10.1016/j.bbr.2022.113879.
Keifer J. Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease. J Neurosci Res
Phillips C. Brain-derived neurotrophic factor, depression, and physical activity: Making the neuroplastic connection. Neural Plast
. doi: 10.1155/2017/7260130.
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
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
: 28. doi: 10.4103/jrms.jrms_823_21.
Hosseini SH, Espahbodi F, Goudarzi SMMM. Citalopram versus psychological training for depression and anxiety symptoms in hemodialysis patients. Iran J Kidney Dis
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
Krapić M, Kavazović I, Wensveen FM. Immunological mechanisms of sickness behavior in viral infection. Viruses
Morris G, Anderson G, Galecki P, Berk M, Maes M. A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC Med
(1). doi: 10.1186/1741-7015-11-64.
Abareshi A, Anaeigoudari A, Norouzi F, Marefati N, Beheshti F, Saeedjalali M, et al. The effects of captopril on lipopolysaccharide-induced sickness behaviors in rats. Vet Res Forum
Beheshti F, Norouzi F, Abareshi A, Anaeigoudari A, Hosseini M. Acute administration of Nigella sativa
showed anxiolytic and anti-depression effects in rats. Curr Nutr Food Sci
Arab Z, Hosseini M, Mashayekhi F, Anaeigoudari A. Zataria multiflora
extract reverses lipopolysaccharide-induced anxiety and depression behaviors in rats. Avicenna J Phytomed
Norouzi F, Abareshi A, Anaeigoudari A, Shafei MN, Gholamnezhad Z, Saeedjalali M, et al. The effects of Nigella sativa
on sickness behavior induced by lipopolysaccharide in male Wistar rats. Avicenna J Phytomed
Samad N, Rao T, Bhatti SA, Imran I. Inhibitory effects of selenium on arsenic-induced anxiety-/depression-like behavior and memory impairment. Biol Trace Elem Res
Chang F, Yeung K, Chan G. Identifying Mercury heavy-metal poisoning masquerading as dementia and Parkinson’s disease-Recognizing neuropsychiatric manifestations and dietary contributors. Can Geriatr Soc J
Benkermiche S, Djemli S, Haloui M, Benabed ML, Tahraoui A. Preventive effects of ginger extract and Nigella sativa
oil on anxiety and depression behavior in Wistar rats exposed to mercuric chloride. Pharmacogn Res
Aboubakr M, Elshafae SM, Abdelhiee EY, Fadl SE, Soliman A, Abdelkader A, et al. Antioxidant and anti-inflammatory potential of thymoquinone and lycopene mitigate the chlorpyrifos-induced toxic neuropathy. Pharmaceuticals
(9): 940. doi: 10.3390/ ph14090940.
Fan Q, Yuan Y, Jia H, Zeng X, Wang Z, Hu Z, et al. Antimicrobial and anti-biofilm activity of thymoquinone against Shigella flexneri. Appi Microbiol Biotechnol
Mostafa HES, Alaa El-Din EA, El-Shafei DA, Abouhashem NS, Abouhashem AA. Protective roles of thymoquinone and vildagliptin in manganese-induced nephrotoxicity in adult albino rats. Environ Sci Pollut Res Int
Maideen NMP. Antidiabetic activity of Nigella sativa
(black seeds) and its active constituent (thymoquinone): A review of human and experimental animal studies. Chonnam Med J
Khattab MM, Nagi MN. Thymoquinone supplementation attenuates hypertension and renal damage in nitric oxide deficient hypertensive rats. Phytother Res
Aktaş İ, Mehmet Gür F. Hepato-protective effects of thymoquinone and beta-aminoisobutyric acid in streptozocin induced diabetic rats. Biotech Histochem
Alam M, Najmi AK, Ahmad I, Ahmad FJ, Akhtar MJ, Imam SS, et al. Formulation and evaluation of nano lipid formulation containing CNS acting drug: Molecular docking, in–vitro
assessment and bioactivity detail in rats. Artif Cells Nanomed Biotechnol
Collins HM, Pinacho R, Ozdemir D, Bannerman DM, Sharp T. Effect of selective serotonin reuptake inhibitor discontinuation on anxiety-like behaviours in mice. J Psychopharmacol
Correia AS, Vale N. Tryptophan metabolism in depression: A narrative review with a focus on serotonin and kynurenine pathways. Int J Mol Sci
Zhou Q, Shi Y, Chen C, Wu F, Chen Z. A narrative review of the roles of indoleamine 2, 3-dioxygenase and tryptophan-2, 3-dioxygenase in liver diseases. Ann Transl Med
(2): 174. doi: 10.21037/atm-20-3594.
Alam M, Zameer S, Najmi AK, Ahmad FJ, Imam SS, Akhtar M. Thymoquinone loaded solid lipid nanoparticles demonstrated antidepressant-like activity in rats via
indoleamine 2, 3-dioxygenase pathway. Drug Res
Alam M, Javed MN, Najmi AK, Ahmad FJ, Imam SS, Akhtar M. Thymoquinone lipid nanoparticles cut the gordian knots of depression via
neuroprotective BDNF and downregulation of neuro-inflammatory NF-κB, IL-6, and TNF-α in LPS treated rats. Curr Drug Metab
Olanrewaju JA, Owolabi JO, Awodein IP, Enya JI, Adelodun ST, Olatunji SY, et al. Zingiber officinale
ethanolic extract attenuated reserpine-induced depression-like condition and associated hippocampal aberrations in experimental Wistar rats. J Exp Pharmacol
Samad N, Manzoor N, Muneer Z, Bhatti SA, Imran I. Reserpine-induced altered neuro-behavioral, biochemical and histopathological assessments prevent by enhanced antioxidant defence system of thymoquinone in mice. Metab Brain Dis
Golden SH, Lazo M, Carnethon M, Bertoni AG, Schreiner PJ, Roux AVD, et al. Examining a bidirectional association between depressive symptoms and diabetes. JAMA
Safhi MM, Qumayri HM, Masmali AU, Siddiqui R, Alam MF, Khan G, et al. Thymoquinone and fluoxetine alleviate depression via
attenuating oxidative damage and inflammatory markers in type-2 diabetic rats. Arch Physiol Biochem
Ma B, Mao Y, Chang L, Dai T, Xin X, Ma F, et al. S-Propargyl-cysteine prevents concanavalin A-induced immunological liver injury in mice. Pharm Biol
Nakagawasai O, Yamada K, Nemoto W, Sato S, Ogata Y, Miya K, et al. Liver hydrolysate attenuates the sickness behavior induced by concanavalin A in mice. J Pharmacol Sci
Nazir S, Farooq RK, Khan H, Alam T, Javed A. Thymoquinone harbors protection against Concanavalin A-induced behavior deficit in BALB/c mice model. J Food Biochem
(3): e13348. doi: 10.1111/jfbc.13348.
Firdaus F, Zafeer MF, Ahmad M, Afzal M. Anxiolytic and anti-inflammatory role of thymoquinone in arsenic-induced hippocampal toxicity in Wistar rats. Heliyon
(6). doi: 10.1016/j.heliyon.2018. e00650.
Dong D, Zhao M, Zhang J, Huang M, Wang Y, Qi L, et al. Neurolytic splanchnic nerve block and pain relief, survival, and quality of life in unresectable pancreatic cancer: A randomized controlled trial. Anesthesiology
Shimo K, Ogawa S, Niwa Y, Tokiwa Y, Dokita A, Kato S, et al. Inhibition of current perception thresholds in A-delta and C fibers through somatosensory stimulation of the body surface. Sci Rep
Roy TK, Uniyal A, Tiwari AV. Multifactorial pathways in burn injury-induced chronic pain: Novel targets and their pharmacological modulation. Mol Biol Rep
2022. doi: 10.1007/s11033-022-07748-9.
Zhang Y, Wang Y, Zhao W, Li L, Li L, Sun Y, et al. Role of spinal RIP3 in inflammatory pain and electroacupuncture-mediated analgesic effect in mice. Life Sci
. doi: 10.1016/j.lfs.2022.120839.
Prado PÁ, Chassot AA, Landra-Willm A, Sandoz G. Regulation of two-pore-domain potassium TREK channels and their involvement in pain perception and migraine. Neurosci Lett
. doi: 10.1016/j.neulet.2022.136494.
Choi SI, Hwang SW. Depolarizing effectors of bradykinin signaling in nociceptor excitation in pain perception. Biomol Ther
Govea RM, Barbe MF, Bove GM. Group IV nociceptors develop axonal chemical sensitivity during neuritis and following treatment of the sciatic nerve with vinblastine. J Neurophysiol
Loyd DR, Henry MA, Hargreaves KM. Serotonergic neuromodulation of peripheral nociceptors. Semin Cell Dev Biol
Crosson T, Wang JC, Doyle B, Merrison H, Balood M, Parrin A, et al. FcεR1-expressing nociceptors trigger allergic airway inflammation. J Allergy Clin Immunol
Kwon J, Choi YI, Jo HJ, Lee SH, Lee HK, Kim H, et al. The role of prostaglandin E1 as a pain mediator through facilitation of hyperpolarization-activated cyclic nucleotide-gated channel 2 via
the EP2 receptor in trigeminal ganglion neurons of mice. Int J Mol Sci
(24). doi: 10.3390/ijms222413534.
Labuz D, Celik MÖ, Seitz V, Machelska H. Interleukin-4 induces the release of opioid peptides from M1 macrophages in pathological pain. J Neurosci
Zhang Q, Ren Y, Mo Y, Guo P, Liao P, Luo Y, et al. Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects. Cell Res
Wen L, Tang L, Zhang M, Wang C, Li S, Wen Y, et al. Gallic acid alleviates visceral pain and depression via
inhibition of P2X7 receptor. Int J Mol Sci
Liu W, Wang CC, Lee KH, Ma X, Kang TL. Research methodology in acupuncture and moxibustion for managing primary dysmenorrhea: A scoping review. Complement Ther Med
. doi: 10.1016/j.ctim.2022.102874.
Itani R, Soubra L, Karout S, Rahme D, Karout L, Khojah HM. Primary dysmenorrhea: Pathophysiology, diagnosis, and treatment updates. Korean J Fam Med
Arabnezhad L, Mohammadifard M, Rahmani L, Majidi Z, Ferns GA, Bahrami A. Effects of curcumin supplementation on vitamin D levels in women with premenstrual syndrome and dysmenorrhea: A randomized controlled study. BMC Complement Med Ther
Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical applications of saffron (Crocus sativus
) and its constituents: A review. Drug Res
Zeru AB, Muluneh MA. Thyme tea and primary dysmenorrhea among young female students. Adolesc Health Med Ther
Samadipour E, Rakhshani MH, Kooshki A, Amin B. Local usage of Nigella sativa
oil as an innovative method to attenuate primary dysmenorrhea: A randomized double-blind clinical trial. Oman Med J
Rafati M, Ghasemi A, Saeedi M, Habibi E, Salehifar E, Mosazadeh M, et al. Nigella sativa
L. for prevention of acute radiation dermatitis in breast cancer: A randomized, double-blind, placebo-controlled, clinical trial. Complement Ther Med
. doi: 10.1016/j.ctim.2019.102205.
Kooshki A, Forouzan R, Rakhshani MH, Mohammadi M. Effect of topical application of Nigella sativa
oil and oral acetaminophen on pain in elderly with knee osteoarthritis: A crossover clinical trial. Electron Physician
Nasuti C, Fedeli D, Bordoni L, Piangerelli M, Servili M, Selvaggini R, et al. Anti-inflammatory, anti-arthritic and anti-nociceptive activities of Nigella sativa
oil in a rat model of arthritis. Antioxidants
Shamsi S, Sultana T, Chowdhury P. Mycoflora associated with Paanch Phoron and its management by common salt. Bangladesh J Sci Res
Gias ZT, Afsana F, Debnath P, Alam MS, Ena TN, Hossain MH, et al. A mechanistic approach to HPLC analysis, antinociceptive, anti-inflammatory and postoperative analgesic activities of panch phoron in mice. BMC Complement Med Ther
Zakaria A, Jais MR, Ishak R. Analgesic properties of Nigella sativa
and Eucheuma cottomi
extracts. J Nat Sci Biol Med
Bashir MU, Qureshi HJ. Analgesic effect of Nigella sativa
seeds extract on experimentally induced pain in albino mice. J Coll Physicians Surg Pak
Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: Clinical manifestations and mechanisms. Lancet Neuro
Tian MM, Li YX, Liu S, Zhu CH, Lan XB, Du J, et al. Glycosides for peripheral neuropathic pain: A potential medicinal components. Molecules
Amin B, Taheri MMH, Hosseinzadeh H. Effects of intraperitoneal thymoquinone on chronic neuropathic pain in rats. Pianta Medica
Tsantoulas C. Emerging potassium channel targets for the treatment of pain. Curr Opin Support Palliai Care
Mohammadi S, Fakhri S, Mohammadi-Farani A, Farzaei MH, Abbaszadeh F. Astaxanthin engages the l-arginine/NO/cGMP/KATP channel signaling pathway toward antinociceptive effects. Behav Pharmacol
Parvardeh S, Sabetkasaei M, Moghimi M, Masoudi A, Ghafghazi S, Mahboobifard F. Role of L
-arginine/NO/cGMP/KATP channel signaling pathway in the central and peripheral antinociceptive effect of thymoquinone in rats. Iran J Basic Med Sci
The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
[Table 1], [Table 2]