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Abstract

Thymoquinone (TQ), one of the main components active of Nigella sativa, exhibited very useful biomedical effects such as anti-inflammatory, antioxidant, antimicrobial, antiparasitic, anticancer, hypoglycemic, antihypertensive, and antiasthmatic effects. There are several studies about pharmacological activities of TQ but its neuroprotection effects are not fully described. The literature search has indicated many studies pertaining to the effects of TQ in neurological problems such as epilepsy, parkinsonism, anxiety, and improvement of learning and memory, and so on. In addition, TQ protected brain cells from various injuries due to its antioxidant, anti-inflammatory, and apoptotic effects in cell line and experimental animal models. The present study has been designed to review the scientific literature about the pharmacological activities of TQ to the neurological diseases. This study purposed that although experimental studies indicated the beneficial effects of TQ against nervous system problems, better designed clinical trials in humans are needed to confirm these effects.

Keywords

neurodegenerative diseases thymoquinone antioxidant anti-inflammation apoptosis

Introduction

Plants as natural producers of chemical compounds are used as traditional medicines for human health.¹ Nigella sativa (of the family Ranunculaceae) is commonly called black cumin, fennel flower, or nutmeg flower. Kalonji seeds² and Ajaji, black caraway seed, and habbatu sawda are other names of N sativa.³ It is considered as a medicinal herb with some religious usage, calling it the “remedy for all diseases except death” (Prophetic hadith)⁴ and Habatul Baraka “the Blessed Seed.”³ The black cumin oil consists of main medicinal components such as tocopherols, phytosterols, polyunsaturated fatty acids, thymoquinone (TQ), ρ-cymene, carvacrol, t-anethole, and 4-terpineol. Thymoquinone (2-isopropyl-5- methyl benzo-1, 4-quinone), the main ingredients of the N sativa seeds, has been found in many medicinal plants such as several genera of the Lamiaceae family (Monarda) and the Cupressaceae family (Juniperus).⁵ Thymoquinone is the main ingredient of the plant, which is effective for treatment of various diseases such as neurodegenerative disorders, coronary artery diseases, and respiratory and urinary system diseases.^6

-13 Thymoquinone has also been indicated to possess antioxidant, anti-inflammation, anticancer, antibacterial, antimutagenic, and antigenotoxic activities.^{9,14

-27} Thymoquinone may be considered as a therapeutic agent for the prevention of oral supplementation of chrysin (100 mg/kg body weight) to hyperammonemic rats, which considerably restored the levels of brain ammonia, water content, and the expressions of glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), tumor necrosis factor α (TNF-α), interleukin (IL) 1β, IL-6, p65, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Our findings provided substantial evidence that the chrysin synergistically attenuates the neuroinflammatory mechanism by repressing the expression of pro-inflammatory cytokines and upregulating the astrocytic protein expressions via ammonia-reducing strategies. These data suggest that TQ effectively acts as a therapeutic agent to treat hyperammonemia-mediated neuroinflammation.

However, the exact mechanism of TQ involved in the prevention of neurodegenerative diseases is still unclear. The present review aimed to critically review the recent study from 1997 to 2017 regarding the protective effects of TQ in the management of neurodegenerative diseases.

Pharmacology Properties

Chemical Structure

Thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) is the most bioactive ingredients of seeds with molecular formula C₁₀H₁₂O₂ and molar mass 164.20 g·mol⁻¹.²⁸ Thymoquinone consists of the enol, keto, and mixture forms. The keto form is the major form that is involved in the pharmacological effects of TQ.²⁹ The sensitivity to light of TQ was high and is deprecated in a short period of light exposure. Furthermore, it was unstable in aqueous solutions, especially at an alkaline pH.³⁰

Pharmacokinetics

The hydrophobic property of TQ limits its bioavailability and drug formulation.³⁰ There are different routes for administration of TQ including intravenous (iv),^31,32 intraperitoneal (ip),^33
-35 and oral subacute and subchronic administration.^33,36

-39 After oral administration, TQ is metabolized via the liver metabolizing enzymes such as DT-diaphorase (a quinine reductase) that modifies TQ into a reduced form thymohydroquinone.⁴⁰ The information about the bioavailability and pharmacokinetic properties of TQ and formulation problems is not sufficient for usage in the clinical trial studies. The clearance rate of TQ after iv administration was 7.19 mL/kg/min, and the estimated volume of distribution at steady state (Vs) was 700.90 mL/kg in the animal model. Following oral exposure, the clearance rate was 12.30 mL/min/kg and Vs was 5109.46 mL/kg. The elimination half-life (T1/2) of TQ was about 217 minutes. In addition, the percentages of TQ protein binding in human and rabbit plasma were 98.99 and 99.19, respectively,⁴¹ which indicates the quick elimination and slow absorption of TQ following oral exposure. It has been indicated that TQ causes complex formation with human serum albumin (HSA), bovine serum albumin (BSA), and α1-acid glycoprotein (AGP) in serum.^42,43 In addition, it was observed that the association between TQ and HSA as well as TQ and AGP does not affect the pharmacological properties of TQ.^42,43 However, the covalent binding of TQ to BSA prevented the TQ anticancer activity against cancer cells.⁴³ The estimated percentages of TQ-protein binding in human and rabbit plasma were 99.19 and 98.99, respectively.⁴¹ In recent years, some analogs of TQ such as molecular micelle-modified poly (d, lactide-co-glycolide) nanoparticles, solid lipid nanoparticles (SLNs), TQ-encapsulated chitosan nanoparticles, TQ-loaded liposomes, caryophyllene and germacryl conjugates, as well as fatty acid conjugates and TQ-loaded nanostructured lipid carriers have been synthesized that may affect its bioavailability and application in clinical phase.

Toxicological Evaluation

One toxicological study indicated that the lethal dose 50 (LD50) of TQ, when injected ip in rats, was 10 mg/kg. Another study indicated that 4, 8, 12.5, 25, and 50 mg/kg ip injection of TQ in mice has no change in the biochemical indices, such as serum alanine transaminase and lactate dehydrogenase (LDH).⁴⁴ However, ip injection of TQ higher than 50 mg/kg to mice was lethal and the LD50 was 90.3 mg/kg.⁴⁴ Several toxicological studies indicated that oral administration of TQ in the range of 10 to 100 mg/kg has no toxic or lethal effects in mice.^45

-49 The maximum tolerated dose of TQ was 22.5 mg/kg in male and 15 mg/kg in female rats when injected ip, whereas in both male and female rats, the dose was 250 mg/kg after oral administration.⁵⁰

Methods

Databases such as PubMed, Science Direct, Scopus, and Google Scholar were searched for the terms of N. sativa, TQ, neuroprotective effects, and different disorders between the years 1979 and 2017 to prepare this review. For validating the plant’s scientific name, Plantlist.org and examine.com were used.

Neuroprotective Effects

Effect on Neuroinflammation

Neuroinflammation is the main factor involved in the pathogenesis of neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Microglia activation is the main factor involved in the ignition and progression of the neuroinflammation by the response to stimuli such as infection, traumatic brain injury (TBI), and so on. Nuclear factor kappa-light-chain-enhancer of activated B cells is a transcription factor that binds to DNA and activates gene transcription, and its activation is related to inflammation in microglia in the central nervous system (CNS).⁵¹ Activated NF-κB induces the pro-inflammatory cytokines,^52
-54 such as iNOS,⁵⁵ COX-2, and microsomal prostaglandin E synthase-1.⁵⁶ In addition, inflammation increases cellular reactive oxygen species production by releasing various NF-κB-mediated pro-inflammatory mediators.⁵⁷ Therefore, inhibition of microglial activation may be effective for neuronal cell survival. In this regard, one study¹⁹ indicated that TQ treatment (2.5, 5, and 10 μM) inhibited the release of TNF-α, IL-6, and IL-1β. Thymoquinone also decreased the release and levels of messenger RNA (mRNA) of TNF-α, IL-6, IL-1β, and prostaglandin E2 (PGE2) in the microglia cells of rats exposed to lipopolysaccharides (LPS; 100 ng/mL). Results showed that TQ treatment (2.5, 5 and 10 μM) inhibited NF-κB-dependent neuroinflammation in BV2 microglia via decreasing iNOS protein levels, κB inhibitor phosphorylation, and binding of NF-κB to the DNA. It also increased nuclear accumulation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) protein, binding of Nrf2 to the antioxidant responsive element (ARE) consensus binding site, and ARE transcriptional activity. These findings suggested that activation of the Nrf2/ARE signaling pathway by TQ resulted in the inhibition of NF-κB-mediated neuroinflammation. Thymoquinone inhibited LPS-induced neuroinflammation through interference with NF-κB signaling in BV2 microglia. Thymoquinone also activated Nrf2/ARE signaling by increasing transcriptional activity of Nrf2, nuclear localization, and DNA binding, as well as increasing protein levels of NAD(P)H: quinone oxidoreductase 1 and Heme oxygenase 1. Suppression of Nrf2 activity through siRNA or with the use of trigonelline resulted in the loss of anti-inflammatory activity by TQ. Taken together, these studies show that TQ inhibits NF-κB-dependent neuroinflammation in BV2 microglia, by targeting antioxidant pathway involving activation of both Nrf2 and ARE. It seems that activation of Nrf2/ARE signaling pathways by TQ probably results in inhibition of NF-κB-mediated neuroinflammation.

Another study⁵⁸ also indicated that TQ (2.5, 5, and 10 μM) prevented neuroinflammation by inhibiting inflammatory mediators nitric oxide (NO), PGE2, TNF-α, and IL-1β production in BV2 microglial cells. It has been found that TQ inhibited LPS-induced inflammatory mediator production by blocking phosphoinositide 3-kinase (PI3K)/protein kinase B or Akt/NF-κB signaling pathway on LPS-stimulated BV2 microglial cells.⁵⁹

Taka et al⁶⁰ also indicated that TQ (0-100 μM) reduced a set of cytokines including IL-6, IL-1β, IL-12p40/70, chemokine (C-C motif) ligand 12 (CCL12)/monocyte chemotactic protein 5 (MCP-5), CCL2/MCP-1, granulocyte colony-stimulating factor (GCSF), and C-X-C motif chemokine 10 (Cxcl 10)/IFN-γ-induced protein 10 (IP-10) in LPS-stimulated BV-2 murine microglia cells in rats.

Effect on Depression

Depression (major depressive disorder) is a serious mood disorder that disturbs normal feel, thinking, and handling daily activities, such as sleeping, eating, or working at least for 2 weeks.^61,62 The Diagnostic and Statistical Manual of Mental Disorders (DSM) is one of the 2 standard classification systems of mental disorders used by mental health professionals. The DSM originated in 1952 (DSM-I); the other widely used system—the International Statistical Classification of Diseases and Related Health Problems (ICD)—for the first time included a section on mental disorders in 1949 (ICD-6). Both the American Psychiatric Association and the World Health Organization are currently working on revisions of the respective classification systems. The inflammatory indices such as C-reactive protein, IL-6, and TNF-α may be involved in the pathogenesis of depression.^63,64 The recent documents indicate that neuroinflammation is involved in depression.⁶⁵ It was indicated medicinal plants such as Nigella sativa might be effective against depression-like behavior in animal models. In this regard, Hosseini et al⁶⁶ studied the effects of hydroalcoholic extract of Nigella sativa and TQ in a model of LPS (100 μg/kg, ip)-induced depression-like behavior in rats. Fifty male rats placed in 5 groups: control, LPS + saline, LPS + Nigella sativa 200 mg/kg, LPS + Nigella sativa 400 mg/kg, and LPS + TQ. Forced swimming test (FST) was performed 3 times for all groups and immobility time was recorded. Separate administration of Nigella sativa and TQ decreased immobility times compared to LPS group; however, co-administration of Nigella sativa (400 mg/kg) and TQ induced lowest immobility times compared to others. In addition, Nigella sativa and TQ improved the crossing number of treated animals in FST. Taken together, Nigella sativa and TQ had protective effects on LPS-induced depression-like behavior in rats. Findings of these studies indicated that TQ improved LPS-induced learning and memory impairments induced by LPS in rats by attenuating the hippocampal cytokine levels and brain tissues oxidative damage.

Effects on Epilepsy

An epileptic seizure is produced by a temporally limited, synchronous electrical discharge of neurons in the brain. It presents as a variable combination of motor, somatosensory, special sensory, autonomic, and/or behavioral disturbances, which arises suddenly and may last for a few seconds or a few minutes. On rare occasions, seizure activity persists for more than 20 minutes and may go on for hours, or even longer, without interruption (status epilepticus [SE]). The epileptic event may affect a circumscribed area of the brain (partial or focal seizures) or both cerebral hemispheres at the same time (generalized seizures). An impairment of consciousness is found in generalized seizures and in the so-called complex focal seizures.⁶⁷ Status epilepticus is a type of seizures that last too long and the patient does not recover between seizures. It is indicated that oxidative stress plays a main role in the pathogenesis of SE.^67,68

The protective effects of TQ on brain injury in a lithium–pilocarpine rat model of SE have been studied. Nrf2 is a key transcription factor involved in the antioxidant response and can thus protect cells from toxic substances and pathogens.^69
-71 This study⁷² indicated that TQ treatment (10 mg/kg ip) decreased brain injuries induced by SE via modulating the Nrf2 signaling pathway involved in the activation of the antioxidant defense system. In addition, the behavioral experiments indicated that TQ also improved learning and memory function.

Another study²⁰ indicated TQ (10 mg/kg ip) prevented epilepsy by decreasing gene expression of NF-κB, which mediates inflammatory reactions, in a lithium–pilocarpine model of SE. Thymoquinone improved electroencephalography profiles, lowered death rate, decreased seizure severity, and improved learning and memory functions.

Temporal lobe epilepsy (TLE) is another type of epilepsy in adults, characterized by neuronal loss,⁷³ reactive astrogliosis,⁷⁴ and enhanced oxidative stress.⁷⁵ One study⁷⁶ indicated that TQ has a protective effect in the intrahippocampal kainate model of TLE in rat. Thymoquinone pretreatment (10 mg/kg) decreased oxidative stress indices such as malondialdehyde (MDA) and nitrate in the hippocampal tissue and severe seizure activity. Thymoquinone also ameliorated astrogliosis and reduction in neurons in cornu ammonis-1 (CA1), CA3, the hilar regions, and mossy fiber sprouting (MFS) in the dentate gyrus of kainate-lesioned rats. This study indicated that the antiepileptogenic effect of TQ may be related to decreasing seizure activity and lipid peroxidation, hippocampal neuronal loss, and MFS and mitigated astrogliosis in the kainate model of TLE.

Thymoquinone administration (40 and 80 mg/kg, ip) prolonged the onset of seizures and decreased the duration of myoclonic seizures in pentylenetetrazole (PTZ)-induced seizure models in mice through opioid receptor-mediated increase in gamma-aminobutyric acid (GABA)ergic tone.³⁶

Ullah et al⁷⁷ studied the effects of TQ and vitamin C against PTZ-induced generalized seizures in rats. Pretreatments with TQ (40 mg/kg, orally [po]) and vitamin C (250 mg/kg ip) or either alone of these drugs ameliorated PTZ-induced seizures and mortality in rats and neurodegeneration in the cells. Furthermore, TQ and vitamin C prolonged the onset of seizures and reduced the high-grade seizures. Both TQ and vitamin C administration ameliorated decreased expression of the gamma-aminobutyric acid B1 receptor, calcium/calmodulin-dependent protein kinase II, inhibition of phosphorylation of cyclic adenosine monophosphate response element-binding protein, decreased Bcl-2 expression, and activated caspase-3 in the cortex and hippocampus in rats. Treatment of mice with TQ (5, 10, and 20 mg/kg ip) along with alternate-day subconvulsive dose of PTZ produced dose-dependent protection against PTZ-induced kindling and learning and memory impairments. Moreover, treatment of mice with TQ (20 mg/kg) inhibited the biochemical alterations induced by PTZ in the brain except the elevation of brain glutamate level. The associated increase in brain inducible NO synthase mRNA and protein expressions was also inhibited. These results suggest that glutamate and subsequent oxidative stress and NO overproduction, via inducible NO synthase, play an important role in the pathophysiology of PTZ-induced kindling and cognitive impairments in mice. Thymoquinone dose dependently protects against PTZ-induced kindling and cognitive impairments. Inhibition of PTZ-induced brain oxidative stress and NO overproduction, via increase in the expression and activity of inducible NO synthase, may play an important role in the neuroprotective action of TQ brain inyurirsnkueryjury Ury action. Also in the stressed mice, TQ (20 mg/kg) showed anxiolytic effects, with a significant decrease in plasma nitrite and reversal of the decreased brain GABA content. Pretreatment with methylene blue enhanced the antianxiety effect of TQ in both unstressed and stressed mice.

For the first time, a pilot trail study⁷⁸ investigated the effects of oral administration of TQ (1 mg/kg po) on seizure frequency in the on children with refractory epilepsy for 2 periods of 4 weeks with 2 weeks. The results indicated that TQ has no effect on neurological function, laboratory variables, or vital signs of children with refractory epilepsy compared with placebo group.

Effect on PD

Parkinson disease is caused by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain and aggregation of α-synuclein (α-SN) in the brain.⁷⁹ In addition, induction of inflammation and oxidative stress response has long been suggested to play the main role in the pathogenesis of PD.⁸⁰ The neuroprotective effects of some flavonoids against oxidative stress in mesencephalic dopamine neurons induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride have been previously indicated.^81

-84

The protective effects of TQ (7.5 and 15 mg/kg, po) in the management of PD in animal models exposed to rotenone have been investigated.⁸⁵ It was indicated that co-administration of TQ with rotenone prevented PD symptoms such as movement failure induced by rotenone during motor assessments in rotarod, rearing, and bar tests. These findings show that TQ effects on ameliorating the PD symptoms induced by rotenone might be associated with the neuroprotective and antioxidant effects of this compound. In addition, TQ decreased prealbumin serum concentration and oxidative stress indices. The results of this study indicated that TQ ameliorated the motor defects in the animal model of PD due to its antioxidant effects. Thymoquinone has been reported to have antioxidant and anti-inflammatory characteristics in vitro and in vivo. Thymoquinone scavenges free radicals, so prevents cell damage against oxidative agents. It was indicated⁸⁶ that TQ (0.01, 0.1, 1, and 10 μM) protected mesencephalic dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death through activation of enzymatic degradation, preservation of mitochondrial function, and inhibition of apoptotic cell death. The TQ significantly protected dopaminergic neurons, decreased the release of LDH, and increased the mitochondrial membrane potential. This study suggested that TQ activated a lysosomal degradative process in dopaminergic neurons and decreased mitochondria-mediated apoptotic cell death. Synapse degeneration is a common finding in patients with neurodegenerative diseases such as PD, AD, and dementia with Lewy bodies (DLB).⁸⁷ Oligomers of α-SN are the main mediators of neuropathology in PD and DLB.⁸⁸ The protective effects of TQ against α SN-induced synaptic toxicity in rat hippocampal and human-induced pluripotent stem cell (hiPSC)-derived neurons have been investigated.⁸⁹ It was observed that TQ (100 nM) protected cultured hippocampal neurons against α-SN-induced synapse damage and decreased synaptophysin level and inhibition of synaptic activity. In addition, TQ protected human hiPSC-derived neurons against inhibition of spontaneous firing activity and restored mutated P123H-induced inhibition of synaptic vesicle recycling in hippocampal neurons. This study suggested that TQ protected human iPSC-derived neurons from α-SN-induced synapse damage in patients with PD or from those with other α-synucleinopathies. Another study⁹⁰ indicated the protective effects of TQ against MPP+- and rotenone-induced cell death in primary dopaminergic cultures. Thymoquinone (0.1 and 1 μM) protected the total number of their neurons against MPP+- and both short- and long-term rotenone toxicity. The other study reports that the SLNs encapsulated TQ (TQ-SLNs; 10 and 20 mg/kg) and TQ suspension (TQ-S; 80 mg/kg)-treated animals showed a significant (P < .01) improvement in the muscle strength, rigidity, movement, and memory performances on 7th- and 14th-day behavioral analysis than TQ-S (40 mg/kg)-treated group. Similarly, TQ-SLNs highly attenuated the levels of oxidative stress markers such as lipid peroxidation, NO, and protein carbonylsin 3-nitropropionic acid (3-NP)-induced animals. Further, TQ-SLNs significantly restores the antioxidant defense system, controls the mitochondrial succinate dehydrogenase inhibition, and alleviates anticholinergic effect upon (3-NP) induction. In addition, TQ-SLNs efficiently protected the striatal structural microelements against 3-NP toxicity, which was confirmed by light microscopic studies. Thus, the researchers collectively suggest that the low dose of TQ-SLNs supplementation is highly sufficient to attain the effect of TQ-S (80 mg/kg) to attenuate behavioral, biochemical, and histological modifications in 3-NP-exposed HD model.

Effects on AD

Alzheimer disease is one of the serious neurodegenerative diseases that leads to brain cells death and causes memory loss and cognitive decline. It seems that the mechanisms for induction of AD are related to the induction of oxidative stress and inflammation.⁹¹ Several studies indicated that treatment with flavonoids may be effective against AD due to their antioxidant effects.⁹¹ Several studies showed that β-amyloid peptides have a major role in the pathogenesis of AD. The protective effect of TQ (0.1, 1, 10, 100 nM) against amyloid β peptide (Aβ_1-42)-induced neurotoxicity has been investigated in rat hippocampal and cortical neurons.⁹¹ Thymoquinone ameliorated Aβ_1-42-induced neurotoxicity and prevented the mitochondrial membrane potential depolarization and finally reduced the oxidative stress. Thymoquinone improved synaptic vesicle recycling inhibition in primary hippocampal and cortical neurons. Thymoquinone also reversed the loss of spontaneous firing activity and inhibited Aβ_1-42 aggregation in vitro. These beneficial effects may contribute to the protection against Aβ-induced neurotoxicity. Therefore, it seems that TQ has neuroprotection potential against Aβ_1-42 in rat hippocampal by ameliorating oxidative stress. The several evidences showed that natural agents that can inhibit the pathways related to Aβ-induced neurotoxicity may be effective in the treatment of AD.^92,93 The neuroprotective effects of TQ against β-amyloid peptide 1 to 40 sequence (Aβ_1-40)-induced neuronal cell death have been investigated in primary cultured cerebellar granule neurons (CGNs).⁹⁴ The pretreatment of CGNs with TQ (0.1 and 1 M) inhibited Aβ_1-40-induced apoptosis of CGNs via both extrinsic and intrinsic caspase pathways. The pretreatment of TQ also decreased LDH release, maintained cell bodies, activated neurite network, improved condensed chromatin, increased free radical production, and inhibited caspase-3, -8, and -9 activation compared to those exposed to Aβ_1-40 alone. These findings confirmed that TQ may be an effective treatment in AD.

The nicotinic acetylcholine receptors (nAChRs) are ion channels distributed in the central or peripheral nervous system. They are receptors of the neurotransmitter acetylcholine and activation of them by agonists mediates synaptic transmission in the neuron and muscle contraction in the neuromuscular junction.⁹⁵ Current studies reveal the relationship between the nAChRs and the learning and memory as well as cognition deficit in various neurological disorders such as AD. There are various subtypes in the nAChR family, and the α7 nAChR is one of the most abundant subtypes in the brain. The α7 nAChR is significantly reduced in the patients with AD and is believed to interact with the Aβ amyloid. Aβ amyloid is co-localized with α7 nAChR in the senile plaque and the interaction between them induces neuron apoptosis and reduction in the α7 nAChR expression. Treatment with α7 agonist in vivo shows its neuron protective and procognition properties and significantly improves the learning and memory ability of the animal models.⁹⁶ PNU-282987 has been shown to be a potent and most specific α7 nAChR agonist. Moreover, PNU had significant effects on memory, thus improving performance. An alternative treatment strategy via compounds known as nicotinic “positive allosteric modulators” (PAMs) has been reported. The PAM of α7 nAChRs is known as PNU-120596.⁹⁷ Recently, studies aimed at investigating the combination of PAM of α7 nAChRs with PNU-282987 (α7 nAChR agonist) or with TQ as a possible treatment for AD in an animal model using histological, histochemical, immunohistochemical, and morphometric methods.

The present study aimed at investigating the combination of PAM of α7 nAChRs with PNU-282987 (α7 nAChR agonist) or with TQ as a possible treatment for AD in an animal model using histological, histochemical, immunohistochemical, and morphometric methods. These findings indicated that the early combined treatment in AD can be more effective than single-drug treatment to improve histological changes. Thymoquinone or α7 nAChR agonist combined with PAM plays more effective in the treatment of AD than TQ alone.

Effect on Ischemia

Transient global cerebral ischemia (forebrain ischemia) causes selective and delayed neuronal cell death.⁹⁸ Oxidative stress is one of the main factors involved in the pathogenesis of cerebral ischemia.⁹⁹ The iNOS is upregulated after ischemia–reperfusion injury (IRI) that causes overproduction of NO. The interaction between NO and superoxide leads to form the peroxynitrite radical that induces neuronal death after cerebral ischemia.¹⁰⁰ One study⁴⁷ investigated whether oral administration of TQ protected rat hippocampus neuron against transient forebrain ischemia. Thymoquinone was administered (5 mg/kg/day po) 5 days before ischemia and continued during the reperfusion time. Thymoquinone decreased the neuronal cell death in the hippocampal CA1 region and MDA level and increased glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities after forebrain ischemia. Thymoquinone also decreased oxidative stress-induced inflammation, prevented iNOS upregulation, and inhibited the formation of peroxynitrite. Another study¹⁰¹ also investigated the effect of TQ (2.5, 5 and 10 mg/kg) and N sativa oil (NSO; 0.048, 0.192, and 0.384 mg/kg) on lipid peroxidation level following global cerebral IRI in rat hippocampus. The results indicated that NSO and TQ protected against IRI by modulating oxidative stress in rat hippocampus.

Effect on TBI

Traumatic brain injury is caused after external force injuries on the brain that is the main cause of morbidity and mortality worldwide.¹⁰² After injury, a series of biochemical processes, such as parenchymal inflammation, free radical production, increased intracellular calcium, and lipid peroxidation, as well as NO production induces neurological impairment.^103
-105 The neuroprotective effects of TQ in a rat model of TBI have been investigated using biochemical and histopathological methods.¹⁰⁶ The researchers indicated that TQ (5 mg/kg ip) had healing effects on neural cells after TBI by reducing MDA levels in the neuronal nuclei and mitochondrial membranes of neurons. Neuron density in contralateral hippocampal regions (CA1, CA2-3, and CA4) 7 days after the trauma decreased significantly in the trauma and TQ-treated groups, compared with that in the control group. Neuron densities in contralateral hippocampal regions (CA1, CA2-3, and CA4) were greater in the TQ-treated group than in the trauma group. Thymoquinone did not increase SOD or GSH peroxidase antioxidant levels. However, TQ decreased the MDA levels.

These results indicate that TQ has a healing effect on neural cells after head injury and this effect is mediated by decreasing MDA levels in the nuclei and mitochondrial membrane of neurons.

Effect on Encephalomyelitis

Encephalomyelitis (EAE) is an autoimmune demyelinating disease of the CNS. It is accepted as an animal model for the human multiple sclerosis.¹⁰⁷ Oxidative stress plays a main role in the pathogenesis of EAE.¹⁰⁸ Based on these, Mohamed et al¹⁰⁹ studied this hypothesis that decreasing oxidative stress might ameliorate symptoms and signs of EAE in animal models. Therefore, TQ (1 mg/kg, injected at tail vein) administration was done for evaluating EAE symptoms in 2 groups of EAE rats (1 group injected at day 1-5 and other group injected at day 7-12). The results indicated that TQ ameliorated hind limb weakness and/or paralysis, tail weakness, perivascular inflammation, and low spinal cord GSH level. However, animals received TQ at day 12 to 17 had higher GSH level, no perivascular inflammation, and no symptoms compared with other groups. This study suggested that TQ improved EAE animals by modulating oxidative stress. Summary of the neuroprotective effects of TQ are shown in Table 1.

Table 1.

A Summary of Neuroprotective Effects of Thymoquinone.

Ext./Cons.	Concentration	Experimental Model	Study Condition	Effects	References
TQ	2.5, 5, and 10 μM	BV2 mouse microglia cell line	LPS-induced neuroinflammation	Inhibition of NF-κB-mediated neuroinflammation by the activation of Nrf2/ARE signaling pathway	¹⁹
				Inhibition of inflammatory mediators (NO, PGE2, TNF-α, and IL-1β) production by blocking PI3K/Akt/NF-κB signaling pathway	⁵⁸
				Attenuating neuroinflammation by decreasing IL-6, IL-1β, IL-12p40/70, CCL12/MCP-5, CCL2/MCP-1, GCSF, and Cxcl10/IP-10	⁶⁰
	0-100 μM	Rat	LPS-induced depression-like behavior	Prevented depression behavior by decreasing immobility time and improving crossing number of animals in FST	⁶⁶
	40 mg/kg		Lithium–pilocarpine model of SE	Prevented epilepsy by modulating Nrf2 signaling pathway involved in the activation of antioxidant defense system	⁷²
	10 mg/kg		Lithium–pilocarpine model of SE	Prevented epilepsy by decreasing gene expression of NF-κB, which mediates inflammatory reactions	²⁰
	10 mg/kg		Intrahippocampal kainate model of TLE	Prevented seizure activity and lipid peroxidation, hippocampal neuronal loss, and MFS and mitigate astrogliosis	⁷⁶
	10 mg/kg		PTZ-induced seizure model	Prolonged the onset of seizures and decreased the duration of myoclonic seizures through an opioid receptor-mediated increase in GABAergic tone	³⁶
	40 and 80 mg/kg		PTZ-induced seizure model	Prolonged the onset of seizures via ameliorating the decreased expression of GABAB1R, CaMKII, inhibition phosphorylation of CREB, decreased Bcl-2 expression, and activated caspase-3	⁷⁷
	40 mg/kg	Human	Intractable seizure model	Has no effect on neurological function, laboratory variables, or vital signs, but was effective and tolerable	⁷⁸
	1 mg/kg	Rat	Rotenone model of PD	Prevented motor defects via ameliorating oxidative stress	⁸⁵
	7.5 and 15 mg/kg	Rat	MPP+-induced cell death	Protected mesencephalic dopaminergic neurons via preservation of mitochondrial function and inhibition of apoptotic cell death	⁸⁶
	0.01, 0.1, 1, and 10 μM	Rat hippocampal and hiPSC	Alpha (SN)-induced synaptic toxicity in rat hippocampal and hiPSC-derived neurons	Protected neurons against inhibition of spontaneous firing activity and restoration of mutated P123H-induced inhibition of synaptic vesicle recycling	⁸⁹
	0.01, 0.1, 1, 10 nM	Mice primary dopaminergic culture	MPP+- and rotenone-induced cell death	Protected primary dopaminergic neuron against MPP+- and rotenone-induced cell death	⁹⁰
	0.1, 1, 10, 100 nM	Rat primary hippocampal and cortical neurons	Aβ_1-42-induced neurotoxicity in hippocampal and cortical neurons	Prevented neurotoxicity induced by Aβ_1-42 via ameliorating oxidative stress	⁹¹
	0.1 and 1 M	CGNs	Aβ_1-40-induced neuronal cell death	Prevented neurotoxicity induced by Aβ_1-40 via inhibiting apoptosis mediated by both extrinsic and intrinsic caspase pathways	⁹⁴
	0.1 and 1 μM	Rat	LPS-mediated AD model	TQ plus PAM treatment in AD can be more effective than single drug treatment	⁹⁷
	5 mg/kg		Transient forebrain ischemia by bilateral occlusion of carotid arteries	Prevented ischemia by decreasing oxidative stress-induced inflammation; increasing GSH, CAT, and SOD activities; preventing iNOS upregulation; inhibiting the formation of peroxynitrite	⁴⁷
	2.5, 5, and 10 mg/kg		Global cerebral IRI	Prevented ischemia by decreasing oxidative stress	¹⁰¹
	5 mg/kg		TBI model	Prevented TBI by reducing the MDA levels in the neuronal nuclei and mitochondrial membranes of neurons	¹⁰⁶
	10 and 20 mg/kg	Mice	Stressed condition by 6-hour immobilization	TQ prevented the feelings of anxiety and fear by modulating NO-cGMP and GABA-ergic pathways which play a main role in the unstressed condition	¹⁰⁷
					¹⁰⁷
	1 mg/kg	Rat	EAE model	TQ prevented EAE by modulating oxidative stress

Abbreviations: TQ, thymoquinone; hiPSC, human-induced pluripotent stem cell-derived neurons; CGNs, cerebellar granule neurons; LPS, lipopolysaccharides; SE, status epilepticus; TLE, temporal lobe epilepsy; PTZ, pentylenetetrazole; PD, Parkinson disease; MPP, 1-methyl-4-phenylpyridinium; Aβ, β-amyloid peptide; AD, Alzheimer disease; IRI, ischemia–reperfusion injury; TBI, traumatic brain injury; EAE, experimental allergic encephalomyelitis; NF-κB, nuclear factor kappa-activated B cells; Nrf2/ARE, nuclear factor (erythroid-derived 2)-like 2; NO, nitric oxide; PGE2, prostaglandin E2; TNF-α, tumor necrosis factor α; IL, interleukin; CCL/MCP, chemokine (C-C motif) ligand monocyte chemoattractant protein; GCSF, granulocyte colony-stimulating factor; Cxcl10/IP-10, C-X-C motif chemokine IFNγ-induced protein 10; PI3K/Akt, phosphoinositide 3-kinase; Cgmp, cyclic guanosine monophosphate; FST, forced swimming test; MFS, mossy fiber sprouting; GABAB1R, gamma-aminobutyric acid B1 receptor; CaMKII, calcium/calmodulin-dependent protein kinase II; CREB, response element-binding protein; GABAergic, gamma-aminobutyric acid; GSH, glutathione; CAT, catalase; SOD, superoxide dismutase; iNOS, inducible nitric oxide synthase nitric oxide; NO, nitric oxide.

Conclusion

Recent studies have been focused on the natural neuroprotective agents due to its low adverse effects with the increase in neurodegenerative diseases. Polyphenols have been considered as the main target for drug design due to the growing evidence that suggests that flavonoids possess beneficial effects on mental diseases. Thymoquinone is an important natural neuroprotective agent that is widely seen in N sativa seeds. The present review indicated the protective effects of TQ in the control of depression, epilepsy, PD, AD, ischemia, TBI, anxiety, encephalomyelitis, and brain cancer that have been found in many experiments and a few clinical trials. The present review suggests an involvement of NO-cGMP and GABAergic pathways in the anxiolytic-like activity of TQ. Thymoquinone also has potential to protect primary dopaminergic neurons against MPP (+) and rotenone relevant to PD. Thymoquinone pretreatment could attenuate seizure activity and lipid peroxidation, lower hippocampal neuronal loss, and mitigate astrogliosis in epilepsy model. Thymoquinone may prevent neurotoxicity and Aβ_1-40-induced apoptosis. Thymoquinone is, therefore, worth studying further for its potential to reduce the risks of developing AD. The neuroprotective effects of TQ may be related to modulatory effects on inflammation, apoptosis, and oxidative stress. The activation of the Nrf2/ARE signaling pathway by TQ resulted in the inhibition of NF-κB-mediated neuroinflammation. In addition, TQ inhibited inflammatory mediator production by blocking PI3K/Akt/NF-κB signaling pathway. Thymoquinone exhibited anti-inflammatory effects by decreasing several cytokines, including TNF-α, NF-κB, IL-6, IL-1β, IL-12p40/70, (CCL12)/MCP-5, (CCL2)/MCP-1, GCSF, and Cxcl 10/IP-10 of, NO, PGE2, and iNOS. Thymoquinone modulates oxidant–antioxidant system by increasing antioxidant content, including GSH, CAT, glutathione S-transferase, and SOD, and decreasing lipid peroxidation in brain tissue. The antianxiety effects of TQ may be related to the modulating effects on NO-cGMP and GABA-ergic pathways. Several studies have pointed out the use of TQ in the management of PD via reducing lack of climbing ability, oxidative stress, and apoptosis in the brain and also AD by decreasing the expression of β-amyloid. The neuroprotective effects of TQ have been shown by experimental studies, but not yet in clinical trials, and more safety studies should be performed to indicate possible toxic effects of TQ in long-term administration in humans. We believe that further preclinical research into the utility of NS and TQ may indicate its usefulness as a potential treatment on neurodegeneration after chronic toluene exposure in rats. In conclusion, this review suggests that the neuroprotective effects of TQ are associated with the antioxidant and anti-inflammatory activities. Although experimental studies indicated the beneficial effects of TQ against nervous system problems, better designed clinical trials in humans are needed to confirm these effects.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ali Mohammad Pourbagher Shahri

References

Dubick

. Historical perspectives on the use of herbal preparations to promote health. J Nutr. 1986;116(7):1348–1354.

Qidwai

Hamza

Qureshi

Gilani

. Effectiveness, safety, and tolerability of powdered Nigella sativa (kalonji) seed in capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults: results of a randomized, double-blind controlled trial. J Altern Complement Med. 2009;15(6):639–644.

Gali-Muhtasib

El-Najjar

Schneider-Stock

. The medicinal potential of black seed (Nigella sativa) and its components. Adv Phytomedicine. 2006;2:133–153.

Ahmad

Husain

Mujeeb

. A review on therapeutic potential of Nigella sativa: a miracle herb. Asian Pac J Trop Biomed. 2013;3(5):337–352.

Taborsky

Kunt

Kloucek

Lachman

Zeleny

Kokoska

. Identification of potential sources of thymoquinone and related compounds in Asteraceae, Cupressaceae, Lamiaceae, and Ranunculaceae families. Open Chem. 2012;10(6):1899–1906.

Hosseinian

Rad

Bideskan

. Thymoquinone ameliorates renal damage in unilateral ureteral obstruction in rats. Pharmacol Rep. 2017;69(4):648–657.

Awad

Kamel

Sherief

MAE

. Effect of thymoquinone on hepatorenal dysfunction and alteration of CYP3A1 and spermidine/spermine N-1-acetyl-transferase gene expression induced by renal ischaemia–reperfusion in rats. J Pharm Pharmacol. 2011;63(8):1037–1042.

Ali

Al Za’abi

Shalaby

. The effect of thymoquinone treatment on the combined renal and pulmonary toxicity of cisplatin and diesel exhaust particles. Exp Bio Med. 2015;240(12):1698–1707.

Ren

Kong

Kang

. Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice. Int Immunopharmacol. 2016;38:70–80.

10.

Kalemci

Micili

Acar

. Effectiveness of thymoquinone in the treatment of experimental asthma. Clin Ter. 2013;164(3):155–158.

11.

Pourgholamhossein

Sharififar

Rasooli

. Thymoquinone effectively alleviates lung fibrosis induced by paraquat herbicide through down-regulation of pro-fibrotic genes and inhibition of oxidative stress. Environ Toxicol Pharmacol. 2016;45:340–345.

12.

Gonca

Kurt

. Cardioprotective effect of thymoquinone: a constituent of Nigella sativa L., against myocardial ischemia/reperfusion injury and ventricular arrhythmias in anaesthetized rats. Pak J Pharma Sci. 2015;28(4):1267–1273.

13.

Cobourne-Duval

Taka

Mendonca

Bauer

Soliman

. The antioxidant effects of thymoquinone in activated BV-2 murine microglial cells. Neurochem Res. 2016;41(12):3227–3238.

14.

Samarghandian

Shoshtari

Sargolzaei

Hossinimoghadam

Farahzad

. Anti-tumor activity of safranal against neuroblastoma cells. Pharmacogn Mag. 2014;10(Suppl 2):S419–S424.

15.

Badary

Abd-Ellah

El-Mahdy

Salama

Hamada

. Anticlastogenic activity of thymoquinone against benzo (a) pyrene in mice. Food Chem Toxicol. 2007;45(1):88–92.

16.

Velagapudi

El-Bakoush

Lepiarz

Ogunrinade

Olajide

. AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia. Mol Cell Biochem. 2017;435(1-2):149–162.

17.

Ozer

Goktas

Toker

. Thymoquinone protects against the sepsis induced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ damage in rats. Pharmacol Rep. 2017;69(4):683–690.

18.

Elsherbiny

Maysarah

El-Sherbiny

Al-Gayyar

. Renal protective effects of thymoquinone against sodium nitrite-induced chronic toxicity in rats: impact on inflammation and apoptosis. Life Sci. 2017;180:1–8.

19.

Velagapudi

Kumar

Bhatia

. Inhibition of neuroinflammation by thymoquinone requires activation of Nrf2/ARE signalling. Int Immunopharmacol. 2017;48:17–29.

20.

Shao

Feng

Xie

. Protective effects of thymoquinone against convulsant activity induced by lithium-pilocarpine in a model of status epilepticus. Neurochem Res. 2016;41(12):3399–3406.

21.

Mostofa

Hossain

Basak

Sayeed

MSB

. Thymoquinone as a potential adjuvant therapy for cancer treatment: evidence from preclinical studies. Front Pharmacol. 2017;8:295.

22.

Barkat

Abul

Ahmad

Khan

Beg

Ahmad

. Insights into the targeting potential of thymoquinone for therapeutic intervention against triple-negative breast cancer. Curr Drug Targets. 2017.

23.

Alobaedi

Talib

Basheti

. Antitumor effect of thymoquinone combined with resveratrol on mice transplanted with breast cancer. Asian Pac J Trop Med. 2017;10(4):400–408.

24.

Rifaioglu

Nacar

Yuksel

. Antioxidative and anti-inflammatory effect of thymoquinone in an acute Pseudomonas prostatitis rat model. Urol Int. 2013;91(4):474–481.

25.

Selçuk

Durgun

Tekin

. Evaluation of the effect of thymoquinone treatment on wound healing in a rat burn model. J Burn Care Res. 2013;34(5): e274–e281.

26.

Inci

Davarci

Inci

. Anti-inflammatory and antioxidant activity of thymoquinone in a rat model of acute bacterial prostatitis. Hum Exp Toxicol. 2013;32(4):354–361.

27.

Dehghani

Hashemi

Entezari

Mohsenifar

. The comparison of anticancer activity of thymoquinone and nanothymoquinone on human breast adenocarcinoma. Iran J Pharma Res. 2015;14(2):539–546.

28.

Tiruppur Venkatachallam

Pattekhan

Divakar

Kadimi

. Chemical composition of Nigella sativa L. seed extracts obtained by supercritical carbon dioxide. J Food Sci Technol. 2010;47(6):598–605.

29.

Alkharfy

Al-Daghri

Al-Attas

Alokail

. The protective effect of thymoquinone against sepsis syndrome morbidity and mortality in mice. Int Immunopharmacol. 2011;11(2):250–254.

30.

Salmani

JMM

Asghar

Zhou

. Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light. Molecules. 2014;19(5):5925–5939.

31.

El Tahir

Ashour

Al-Harbi

. The cardiovascular actions of the volatile oil of the black seed (Nigella sativa) in rats: elucidation of the mechanism of action. Gen Pharmacol. 1993;24(5):1123–1131.

32.

El Tahir

Ashour

Al-Harbi

. The respiratory effects of the volatile oil of the black seed (Nigella sativa) in guinea-pigs: elucidation of the mechanism (s) of action. Gen Pharmaco. 1993;24(5):1115–1122.

33.

Abdel-Fattah

A-FM

Matsumoto

Watanabe

. Antinociceptive effects of Nigella sativa oil and its major component, thymoquinone, in mice. Eur J Pharmacol. 2000;400(1):89–97.

34.

El Gazzar

El Mezayen

Marecki

Nicolls

Canastar

Dreskin

. Anti-inflammatory effect of thymoquinone in a mouse model of allergic lung inflammation. Int Immunopharmacol. 2006;6(7):1135–1142.

35.

El-Mahmoudy

Shimizu

Shiina

Matsuyama

El-Sayed

Takewaki

. Successful abrogation by thymoquinone against induction of diabetes mellitus with streptozotocin via nitric oxide inhibitory mechanism. Int Immunopharmacol. 2005;5(1):195–207.

36.

Hosseinzadeh

Parvardeh

. Anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, in mice. Phytomed. 2004;11(1):56–64.

37.

Nagi

Alam

Badary

Al-Shabanah

Al-Sawaf

Al-Bekairi

. Thymoquinone protects against carbon tetrachloride hetatotoxicity in mice via an antioxidant mechanism. IUBMB Life. 1999;47(1):153–159.

38.

Pari

Sankaranarayanan

. Beneficial effects of thymoquinone on hepatic key enzymes in streptozotocin–nicotinamide induced diabetic rats. Life Sci. 2009;85(23):830–834.

39.

Al-Shabanah

Badary

Nagi

Al-Gharably

Al-Rikabi

Al-Bekairi

. Thymoquinone protects against doxorubicin-induced cardiotoxicity without compromising its antitumor activity. J Exp Clin Cancer Res. 1998;17(2):193–198.

40.

Nagi

Almakki

. Thymoquinone supplementation induces quinone reductase and glutathione transferase in mice liver: possible role in protection against chemical carcinogenesis and toxicity. Phytother Res. 2009;23(9):1295–1298.

41.

Alkharfy

Ahmad

Khan

Al-Shagha

. Pharmacokinetic plasma behaviors of intravenous and oral bioavailability of thymoquinone in a rabbit model. Eur J drug Metab Pharmacokinet. 2015;40(3):319–323.

42.

Lupidi

Scire

Camaioni

. Thymoquinone, a potential therapeutic agent of Nigella sativa, binds to site I of human serum albumin. Phytomed. 2010;17(10):714–720.

43.

El-Najjar

Ketola

Nissilä

. Impact of protein binding on the analytical detectability and anticancer activity of thymoquinone. J Chem Biol. 2011;4(3):97–107.

44.

Mansour

Ginawi

El-Hadiyah

El-Khatib

Al-Shabanah

Al-Sawaf

. Effects of volatile oil constituents of Nigella sativa on carbon tetrachloride-induced hepatotoxicity in mice: evidence for antioxidant effects of thymoquinone. Res Commun Mol Path Pharmacol. 2001;110(3-4):239–252.

45.

Kanter

. Thymoquinone attenuates lung injury induced by chronic toluene exposure in rats. Toxicol Ind Health. 2011;27(5):387–395.

46.

El-Saleh

Al-Sagair

Al-Khalaf

. Thymoquinone and Nigella sativa oil protection against methionine-induced hyperhomocysteinemia in rats. Int J Cardiol. 2004;93(1):19–23.

47.

Al-Majed

Al-Omar

Nagi

. Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. Eur J Pharmacol. 2006;543(1):40–47.

48.

Kanter

. Nigella sativa and derived thymoquinone prevents hippocampal neurodegeneration after chronic toluene exposure in rats. Neurochem Res. 2008;33(3):579.

49.

Mansour

Nagi

El-Khatib

Al-Bekairi

. Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action. Cell Biochem Funct. 2002;20(2):143–151.

50.

Abukhader

. The effect of route of administration in thymoquinone toxicity in male and female rats. Indian J Pharma Sci. 2012;74(3):195.

51.

Farkhondeh

Samarghandian

Azimin-Nezhad

Samini

. Effect of chrysin on nociception in formalin test and serum levels of noradrenalin and corticosterone in rats. Int J Clin Exp Med. 2015;8(2):2465–2470.

52.

Boskabady

Karimi

Samarghandian

Farkhondeh

. Tracheal responsiveness to methacholine and ovalbumin; and lung inflammation in guinea pigs exposed to inhaled lead after sensitization. Ecotoxicol Environ Saf. 2012;86:233–238.

53.

Jana

Dasgupta

Liu

Pahan

. Regulation of tumor necrosis factor-α expression by CD40 ligation in BV-2 microglial cells. J Neurochem. 2002;80(1):197–206.

54.

Zhang

Jiang

. Neuroinflammation in Alzheimer’s disease. Neuropsychiatr Dis Treat. 2015;11:243–256.

55.

Samarghandian

Borji

Afshari

Delkhosh

gholami

. The effect of lead acetate on oxidative stress and antioxidant status in rat bronchoalveolar lavage fluid and lung tissue. Toxicol Mech Methods. 2013;23(6):432–436.

56.

Samarghandian

Azimi-Nezhad

Borji

Hasanzadeh

Jabbari

Farkhondeh

Samini

. Inhibitory and cytotoxic activities of chrysin on human breast adenocarcinoma cells by induction of apoptosis. Pharmacogn Mag. 2016; 12(4):S436–S440.

57.

Samarghandian

Shoshtari

Sargolzaei

Hossinimoghadam

Farahzad

. Anti-tumor activity of safranal against neuroblastoma cells. Pharmacogn Mag. 2014; 10(2):S419–424.

58.

Wang

Gao

Zhang

Fang

. Thymoquinone inhibits lipopolysaccharide-induced inflammatory mediators in BV2 microglial cells. Int Immunopharmacol. 2015;26(1):169–173.

59.

Jayasooriya

RGPT

Lee

K-T

Kang

C-H

. Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt-mediated nuclear transcription factor-κB pathway. Nutr Res. 2014;34(12):1111–1119.

60.

Taka

Mazzio

Goodman

. Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells. J Neuroimmunol. 2015;286:5–12.

61.

Spitzer

Kroenke

Linzer

. Health-related quality of life in primary care patients with mental disorders: results from the PRIME-MD 1000 Study. JAMA. 1995;274(19):1511–1517.

62.

Sharp

Lipsky

. Screening for depression across the lifespan: a review of measures for use in primary care settings. Am Fam Physician. 2002;66(6):1001–1008.

63.

Howren

Lamkin

Suls

. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71(2):171–186.

64.

Dowlati

Herrmann

Swardfager

. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446–457.

65.

Hashioka

. Antidepressants and neuroinflammation: can antidepressants calm glial rage down? Mini Rev Med Chem. 2011;11(7):555–564.

66.

Hosseini

Zakeri

Khoshdast

. The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide-induced depression like behavior in rats. J Pharm Bioallied Sci. 2012;4(3):219–225.

67.

Morimoto

Hashimoto

Kitaoka

Kyotani

. Impact of oxidative stress and newer antiepileptic drugs on the albumin and cortisol value in severe motor and intellectual disabilities with epilepsy. J Clin Med Res. 2018;10(2):137–145

68.

Liu

Wang

Huang

Xue

Hao

. Oxidative stress mediates hippocampal neuron death in rats after lithium–pilocarpine-induced status epilepticus. Seizure. 2010;19(3):165–172.

69.

Espinosa-Diez

Miguel

Mennerich

. Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol. 2015;6:183–197.

70.

Wang

W-P

Zhang

G-L

. Activation of Nrf2-ARE signal pathway in hippocampus of amygdala kindling rats. Neurosci Lett. 2013;543:58–63.

71.

Wang

Zhang

. Activation of Nrf2-ARE signal pathway protects the brain from damage induced by epileptic seizure. Brain Res. 2014;1544:54–61.

72.

Shao

Y-Y

Huang

Y-M

Luo

Xie

Y-M

Chen

Y-H

. Thymoquinone attenuates brain injury via an antioxidative pathway in a status epilepticus rat model. Transl Neurosci. 2017;8(1):9–14.

73.

Jokeit

Schacher

. Neuropsychological aspects of type of epilepsy and etiological factors in adults. Epilepsy Behav. 2004;5(suppl 1):S14–S20.

74.

Xie

Sun

Qiao

. Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy. PLoS One. 2011;6(9):e24966.

75.

Baluchnejadmojarad

Roghani

. Coenzyme q10 ameliorates neurodegeneration, mossy fiber sprouting, and oxidative stress in intrahippocampal kainate model of temporal lobe epilepsy in rat. J Mol Neurosci. 2013;49(1):194–201.

76.

Dariani

Baluchnejadmojarad

Roghani

. Thymoquinone attenuates astrogliosis, neurodegeneration, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. J Mol Neurosci. 2013;51(3):679–686.

77.

Ullah

Badshah

Naseer

Lee

Kim

. Thymoquinone and vitamin C attenuates pentylenetetrazole-induced seizures via activation of GABAB1 receptor in adult rats cortex and hippocampus. Neuromol Med. 2015;17(1):35–46.

78.

Akhondian

Kianifar

Raoofziaee

Moayedpour

Toosi

Khajedaluee

. The effect of thymoquinone on intractable pediatric seizures (pilot study). Epilepsy Res. 2011;93(1):39–43.

79.

Venda

Cragg

Buchman

, Wade-Martins R. α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci. 2010;33(12):559–568.

80.

Mosley

Benner

Kadiu

. Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson’s disease. Clin Neurosci Res. 2006;6(5):261–281.

81.

Muralikrishnan

Samantaray

Mohanakumar

. d-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity. Synapse. 2003;50(1):7–13.

82.

Youdim

Arraf

. Prevention of MPTP (N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax. Neuropharmacology. 2004;46(8):1130–1140.

83.

Muralikrishnan

Mohanakumar

. Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J. 1998;12(10):905–912.

84.

X-P

. Neuroprotective effect of kaempferol against a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Biol Pharma Bull. 2011;34(8):1291–1296.

85.

Ebrahimi

Oryan

Izadpanah

Hassanzadeh

. Thymoquinone exerts neuroprotective effect in animal model of Parkinson’s disease. Toxicol Lett. 2017;276:108–114.

86.

Radad

Al-Shraim

Moustafa

Rausch

W-D

. Neuroprotective role of thymoquinone against 1-methyl-4-phenylpyridinium-induced dopaminergic cell death in primary mesencephalic cell culture. Neurosci. 2015;20(1):10.

87.

Galvin

Uryu

Lee

VM-Y

Trojanowski

. Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains α-, β-, and γ-synuclein. Proc Nati Acad Sci U S A. 1999;96(23):13450–13455.

88.

Kazantsev

Kolchinsky

. Central role of α-synuclein oligomers in neurodegeneration in Parkinson disease. Arch Neurol. 2008;65(12):1577–1581.

89.

Alhebshi

Odawara

Gotoh

Suzuki

. Thymoquinone protects cultured hippocampal and human induced pluripotent stem cells-derived neurons against α-synuclein-induced synapse damage. Neurosci Lett. 2014;570:126–131.

90.

Radad

Moldzio

Taha

Rausch

. Thymoquinone protects dopaminergic neurons against MPP+ and rotenone. Phytother Res. 2009;23(5):696–700.

91.

Alhebshi

Gotoh

Suzuki

. Thymoquinone protects cultured rat primary neurons against amyloid β-induced neurotoxicity. BioChem Biophys Res Commun. 2013;433(4):362–367.

92.

Farías

Guzmán-Martínez

Delgado

Maccioni

. Nutraceuticals: a novel concept in prevention and treatment of Alzheimer's disease and related disorders. J Alzheimers Dis. 2014;42(2):357–367.

93.

Otaegui-Arrazola

Amiano

Elbusto

Urdaneta

Martínez-Lage

. Diet, cognition, and Alzheimer's disease: food for thought. Eur J Nutr. 2014;53(1):1–23.

94.

Ismail

Mazlan

. Thymoquinone prevents β-amyloid neurotoxicity in primary cultured cerebellar granule neurons. Cell Mol Neurobiol. 2013;33(8):1159–1169.

95.

Callahan

Hutchings

Kille

Chapman

Terry

. Positive allosteric modulator of alpha 7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Neuropharmacol. 2013;67:201–212.

96.

Vicens

Ribes

Heredia

Torrente

Domingo

. Effects of an alpha7 nicotinic receptor agonist and stress on spatial memory in an animal model of Alzheimer’s disease. Biomed Res Int. 2013;2013:952719.

97.

Fattah

LIA

Zickri

Aal

Heikal

Osama

. The effect of thymoquinone, α7 receptor agonist and α7 receptor allosteric modulator on the cerebral cortex in experimentally induced Alzheimer’s disease in relation to MSCs activation. Int J Stem Cells. 2016;9(2):230–238.

98.

Petito

Feldmann

Pulsinelli

Plum

. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology. 1987;37(8):1281–1281.

99.

Chan

. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001;21(1):2–14.

100.

Evans

. Free radicals in brain metabolism and pathology. Br Med Bull. 1993;49(3):577–587.

101.

Hosseinzadeh

Parvardeh

Asl

Sadeghnia

Ziaee

. Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomed. 2007;14(9):621–627.

102.

Unterberg

Stover

Kress

Kiening

. Edema and brain trauma. Neurosci. 2004;129(4):1019–1027.

103.

Demir

Kiymaz

Gudu

. Study of the neuroprotective effect of ginseng on superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in experimental diffuse head trauma. Acta Neurochir. 2013;155(5):913–922.

104.

Juurlink

Paterson

. Review of oxidative stress in brain and spinal cord injury: suggestions for pharmacological and nutritional management strategies. J Spinal Cord Med. 1998;21(4):309–334.

105.

Aarabi

Long

. Dynamics of cerebral edema: the role of an intact vascular bed in the production and propagation of vasogenic brain edema. J Neurosurg. 1979;51(6):779–784.

106.

Gülşen

Çölçimen

. Neuroprotective effects of thymoquinone on the hippocampus in a rat model of traumatic brain injury. World Neurosurg. 2016;86:243–249.

107.

Constantinescu

Farooqi

O’brien

Gran

. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079–1106.

108.

Gilgun-Sherki

Melamed

Offen

. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurology. 2004;251(3):261–268.

109.

Mohamed

Shoker

Bendjelloul

. Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor. Biomed Sci Instrum. 2003;39:440–445.

The Neuroprotective Effects of Thymoquinone: A Review

Abstract

Keywords

Introduction

Pharmacology Properties

Chemical Structure

Pharmacokinetics

Toxicological Evaluation

Methods

Neuroprotective Effects

Effect on Neuroinflammation

Effect on Depression

Effects on Epilepsy

Effect on PD

Effects on AD

Effect on Ischemia

Effect on TBI

Effect on Encephalomyelitis

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References