Journal of Neuroimmunology 324 (2018) 54–75

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Journal of Neuroimmunology

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Review Article Therapeutic potentials of ginger for treatment of Multiple sclerosis: A review with emphasis on its immunomodulatory, anti-inflammatory and anti- T oxidative properties ⁎ Abdollah Jafarzadeha,b, , Maryam Nematic a Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran b Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran c Department of Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran

ARTICLE INFO ABSTRACT

Keywords: Multiple sclerosis (MS) is characterized by chronic inflammatory response-induced demyelination of the neurons Ginger and degeneration of the axons within the central nervous system (CNS). A complex network of im- Multiple sclerosis munopathological-, inflammatory- and oxidative parameters involve in the development and advancement of Experimental autoimmune encephalomyelitis MS. The anti-inflammatory, immunomodulatory and anti-oxidative characteristics of the ginger and several of its Therapeutic potentials components have been indicated in some of experimental and clinical investigations. The possible therapeutic potentials of ginger and its ingredients in the treatment of MS may exert mainly through the regulation of the Th1-, Th2-, Th9-, Th17-, Th22- and Treg cell-related immune responses, down-regulation of the B cell-related immune responses, modulation of the macrophages-related responses, modulation of the production of pro- and anti-inflammatory cytokines, down-regulation of the arachidonic acid-derived mediators, interfering with the toll like receptor-related signaling pathways, suppression of the inflammasomes, down-regulation of the oxi- dative stress, reduction of the adhesion molecules expression, and down-regulation of the expression of the chemokines and chemokine receptors. This review aimed to provide a comprehensive knowledge regarding the immunomodulatory-, anti-inflammatory and anti-oxidative properties of ginger and its components, and

Abbreviations: AP-1, Activator protein 1; APCs, Antigen-presenting cells; ASC, apoptosis speck-like protein containing CARD; BAFF, B cell-activating factor be- longing to the TNF family; BALF, Bronchoalveolar lavage fluid; BBB, Blood-brain barrier; BDNF, Brain-derived neurotrophic factor; CAM, Complementary and alternative medicine; CAT, Catalase; CCL, Chemokine (C-C motif) ligand; CCR, CC chemokine receptor; CXCR, C-X-C chemokine receptor; CIS, Clinically-isolated syndrome; CNS, Central nervous system; Con A, Concanavalin A; COX, Cyclooxygenase; cPLA2, Cytosolic phospholipase A2; CREB, cAMP response element binding protein; CXCL, Chemokine (C-X-C motif) ligand; DAMP, Damage-associated molecular patterns; DCs, Dendritic cells; EBI3, Epstein-Barr Virus Induced Gene-3; EAE, Experimental autoimmune encephalomyelitis; ERK, Extracellular signal-regulated kinase; FDA, Food and Drug Administration; FOXP3, Forkhead box P3; GATA-3, GATA binding protein 3; GDNF, Glial cell-derived neurotrophic factor; GM-CSF, Granulocyte-macrophage colony-stimulating factor; G-CSF, Granulocyte-colony stimulating factor; GPX, Glutathione peroxidase; GR, Glutathione reductase; GSH, Glutathione; GST, Glutathione S-transferase; HAMP, Homeostasis-altering mo- lecular processes; HMGB1, High mobility group box 1; HO-1, Heme oxygenase-1; Hs-CRP, High sensitivity C-reactive protein; HSP, Heat shock proteins; ICAM, Intercellular adhesion molecule; IFN, Interferon; Ig, Immunoglobulin; IKK, IκB kinase; IL, Interleukin; iNOS, inducible nitric oxide synthase; IPEX, Immune-dysre- gulation, polyendocrinopathy, enteropathy, and X-linked inheritance syndrome; IRAK, Interleukin-1 receptor-associated kinase; IRF, Interferon regulatory factors; JNK, c-Jun N-terminal kinase; LPS, Lipopolysaccharide; LRR, Leucine-rich repeats; LTs, leukotrienes; LOX, Lipooxygenase; MAPK, Mitogen-activated protein kinase; MCP1, Monocyte chemoattractant protein 1; MDA, Malonaldehyde; MHC, Major histocompatibility complex; MLC, Mixed lymphocyte culture; MLR, Mixed lym- phocyte reaction; MMCS, Maximum mean clinical score; MMP, Matrix metalloproteinase; NEMO, NF-κB essential modulator; NF-κB, Nuclear factor kappa-light chain- enhancer of activated B cells; NGF, Nerve growth factor; NIK, NF-κB inducing kinase.; NLRP3, NLR family pyrin domain containing 3; NO, Nitric oxid; NOX4, NADPH oxidase 4; Nrf2, Nuclear factor erythroid 2–related factor 2; NQO1, Quinone oxidoreductase 1; MS, Multiple sclerosis; MyD88, Myeloid differentiation factor 88; OCBs, Oligoclonal bands; OVA, Ovalbumin; PAMP, Pathogen-associated molecular patterns; PGs, Prostaglandins; PPMS, Primary progressive multiple sclerosis; PRMS, Progressive-relapsing multiple sclerosis; PRRs, Pathogen recognition receptors; SPMS, Secondary progressive multiple sclerosis; RAGE, Receptor for advanced glycation end products; RANTES, Regulated on activation, normal T cell expressed and secreted; RIPK, Receptor-interacting serine/threonine-protein kinase; QR, quinine reductase; RNS, Reactive nitrogen species; RORγt, Retinoic acid-related orphan receptor gamma t; ROS, Reactive oxygen species; RRMS, Relapsing-remitting multiple sclerosis; SOD, Superoxide dismutase; STAT, Signal transducer and activator of transcription; TAB, TAK1-binding protein; TAK1, TGF-β activated kinase 1; T-bet, T box expressed in T cells; TGF-β, Transforming growth factor-β; TIR, Toll/interleukin-1 receptor domain; TLRs, Toll-like receptors; TNF-α, Tumor necrosis factor-α; TRAF, TNF receptor associated factor; Treg cells, Regulatory T cells; TRIF, TIR-domain-containing adapter-inducing interferon-β; Trx, Thioredoxin; VCAM- 1, Vascular cell adhesion molecule ⁎ Corresponding author at: Department of Immunology, Medical School, Kerman University of Medical Sciences, Kerman, Iran. E-mail address: [email protected] (A. Jafarzadeh). https://doi.org/10.1016/j.jneuroim.2018.09.003 Received 27 May 2018; Received in revised form 24 August 2018; Accepted 10 September 2018 0165-5728/ © 2018 Elsevier B.V. All rights reserved. A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

highlight novel insights into the possible therapeutic potentials of this plant for treatment of MS. The review encourages more investigations to consider the therapeutic potentials of ginger and its effective components for managing of MS.

1. Introduction nutritional supplementation was considered with some beneficial im- pacts in MS patients (Kes et al., 2013). As some plant-derived compo- Multiple sclerosis (MS) is characterized by autoimmune and chronic nents have considerable anti-inflammatory and immunomodulatory inflammatory response-induced demyelination of the neurons and de- properties with low side effects, they may have potential to attenuate generation of the axons within the central nervous system (CNS) (Milo symptoms in MS patients. There is no a comprehensive image regarding and Miller, 2014). The clinical exhibitions and courses of MS are the anti-inflammatory, immunomodulatory and anti-oxidative effects of variable, however, several disease patterns have been recognized, in- ginger and its ingredients, and their possible role in protection against cluding relapsing-remitting (RRMS), primary progressive (PPMS), sec- MS. In this review, we provide comprehensive information concerning ondary progressive (SPMS), progressive-relapsing (PRMS) and clini- the immunomodulatory, anti-inflammatory and anti-oxidative proper- cally-isolated syndrome (CIS) (Milo and Miller, 2014). ties of ginger and its components, and highlight the novel insights into Experimental autoimmune encephalomyelitis (EAE) is currently the possible therapeutic capabilities of ginger for treatment of MS. induced in susceptible rodents either by immunization with myelin antigens (active EAE) or by the transfer of the stimulated CD4+ T- 3. Phytochemical ingredients of ginger helper (Th) cells against myelin (Sallusto et al., 2012). There is also evidence suggest that B cells actively participate in the EAE patho- Ginger, the rhizome of Zingiber officinale Roscoe (a member be- genesis, such as B cell-deficient mice were protected against EAE in- longing to the Zingiberaceae family) are commonly used as a spice or duction or EAE could be induced by the transfer of myelin-specific dietary supplement with a long history of utilization in the traditional antiserum (Ray et al., 2011). EAE is a reliable model for studying of the medicine (Mohd Yusof, 2016). About 400 kinds of ingredients have MS pathogenesis and testing of the developing drugs. Indeed, a large been identified in the ginger, however, the pharmacological effects of number of the drugs that are commonly used for MS treatment have ginger are largely attributed to the gingerols, shogaols, zingerone and been evaluated or validated based on the EAE investigations (Baker and paradols (Prasad and Tyagi, 2015). 6-Gingerol is a main pungent Amor, 2014, Constantinescu et al., 2011). component in fresh ginger that attenuates a number of chronic dis- orders in animal models and humans (Choi et al., 2018). After dehy- 2. Immunopathology of multiple sclerosis dration, the 6-gingerol is converted to 6-shogaol which is more stable and has more powerful pharmacological effects than 6-gingerol (Kou Inflammation, a hallmark of MS, is powerfully related with the et al., 2018). 6-Paradol is synthesized from 6-shogaol by microbial demyelination and neurodegeneration in all stages of MS, but it is more metabolism that possess anti-oxidative and anti-inflammatory proper- considerable in the acute and relapsing phases (Yadav et al., 2015). The ties similar to 6-shogaol (Choi et al., 2018, Mohd Yusof, 2016). Zin- infiltration of the various types of leukocytes (including neutrophils, gerone is synthesized from gingerols by the reverse aldolization process DCs, macrophage, CD4+ T cells, CD8+ T cells) happens within the CNS when heating the fresh ginger (Choi et al., 2018). A vast board of and it is postulated that the myelin-reactive CD4+ T cells perform a key pharmacological actions was attributed to the zingerone such as anti- role in the demyelination of neurons and axonal damages (Fletcher inflammatory, anti-oxidant, anti-tumorgenic, anti-hyperlipidemia, and et al., 2010, Yadav et al., 2015). The peripheral stimulation and sub- anti-bacterial activities (Choi et al., 2018). sequent movement of the self-reactive CD4+ T cells into the CNS are The beneficial influences of ginger and its ingredients were in- essential steps in the MS pathogenesis (Yadav et al., 2015). The DCs also dicated in a vast range of the clinical and experimental inflammatory migrate across the damaged blood-brain barrier (BBB) and promote the disorders that are explored in the next sections. In addition, we have polarization of the myelin specific naïve T lymphocytes to the various recently indicated for the first time the beneficial influences of ginger effector T cell subsets such as Th1-, Th2-, Th9-, Th17-, Th22- and Treg on the clinical-, immunological- and inflammatory-related parameters cells (Buc, 2013, Raphael et al., 2015). The immunopathological pro- in EAE disease, as a MS animal model (Jafarzadeh et al., 2017a, cess in MS and EAE is directed by the pathogenic form of Th1- and Th17 Jafarzadeh et al., 2017b, Jafarzadeh et al., 2015a, Jafarzadeh et al., cells (Buc, 2013, Raphael et al., 2015), whereas Treg cells exert pro- 2014d). tective influences against autoimmune diseases (Buc, 2013, Jafarzadeh et al., 2016). The involvement of the Th2 cells in the MS development 4. Beneficial impacts of ginger on the EAE-related clinico- remains mysterious (Buc, 2013, Raphael et al., 2015). Moreover, sev- pathological parameters eral kinds of the CNS residential cells (such as microglia and astrocytes) also contribute in the MS and EAE pathogenesis through the releasing of Ginger has a vast board of anti-inflammatory, immunomodulatory pro-inflammatory cytokines and chemokines (Peterson and Fujinami, and anti-oxidative effects (Table 1 and Fig. 1). The helpful impacts of 2007). The loss of the peripheral tolerance result in the activation and the ginger and its ingredients were indicated in patients with osteoar- expansion of the myelin-reactive Th1/Th17 cells, and cause the auto- thritis (Mozaffari-Khosravi et al., 2016), rheumatoid arthritis (Al- reactive B-cell proliferation (Yadav et al., 2015). Then, the BBB is also Nahain et al., 2014, Ramadan and El-Menshawy, 2013), type 2 diabetes disrupted, which in turn cause the leukocyte aggregation into the CNS (Priya Rani et al., 2011), respiratory distress (Vahdat Shariatpanahi parenchyma and subsequent neuroinflammation, demyelination, and et al., 2013), liver disease (Rahimlou et al., 2016) and primary dys- neurodegeneration (Yadav et al., 2015). menorrheal (Rahnama et al., 2012). The anti-inflammatory activities of Currently, more than ten FDA-approved drugs are used for the MS ginger or its constituents were also indicated in animal model of dis- treatment that all of them influencing the immune system (Baecher- eases such as airway inflammation (Kuo et al., 2011), ulcerative colitis Allan et al., 2018). However, two major considerations regarding the (Zhang et al., 2017), lipopolysaccharide (LPS)-mediated liver failure MS treatment include the drug efficacy and side effects (Baecher-Allan (Lee et al., 2018), neuroinflammation (Ha et al., 2012), neuropathic et al., 2018, Namjooyan et al., 2014). Therefore, there is a necessity for pain (Gopalsamy et al., 2017), fibromyalgia syndrome (Montserrat-de novel therapies that may consider as complementary and alternative la Paz et al., 2018) and peptic ulcers (Wang et al., 2011). The protective treatments. The complementary and alternative medicine (CAM) using impacts of the ginger against several neurological abnormalities,

55 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

Table 1 including epilepsy, migraine, Alzheimer's disease and Parkinson's dis- The immunomodulatory, anti-inflammatory and anti-oxidative activities of ease were also reported (Choi et al., 2018). ginger and its components. Jafarzadeh and colleagues firstly indicated the beneficial effects of fl Down-regulation of the Th1 cell-related immune responses the ginger on the clinical-, immunological- and in ammatory-related Differentiation of Th1 cells↓ Expression of IFN-γ↓ parameters in EAE (Jafarzadeh et al., 2014d). It was observed that the Expansion of Th1 cells ↓ Expression of IL-2↓ clinical symptoms of EAE were appeared on day 10 after EAE induction, ↓ α↓ Expression of IL-12 Expression of TNF- while ginger-treated EAE mice displayed the clinical signs later, at days Modulation of the Th2 cell-related immune responses 14 and 15 post disease induction (Jafarzadeh et al., 2014d). The clinical ff ↓ ↓ Di erentiation of Th2 cells Expression of IL-4 scores were also significantly diminished in EAE mice treated with Expansion of Th2 cells↓ IgE production↓ Antibody production↓ Severity of the allergic diseases↓ ginger in comparison with untreated control EAE mice (Jafarzadeh et al., 2014d). In addition, the untreated EAE mice displayed a large Down-regulation of the Th17 cell-related immune responses infiltration of the inflammatory cells in their CNS, whereas treatment Differentiation of Th17 cells↓ Expression of IL-17↓ fi Expression of IL-23↓ Expression of IL-6↓ with the ginger lessened the in ltration process (Jafarzadeh et al., 2014d). The histopathological scores of spinal cords for ginger-treated Up-regulate of the Treg cell-related immune responses Expression of TGF-β↑ Expression of IL-10↑ EAE group was lower than untreated EAE group (Jafarzadeh et al., 2014d). The body weight was reduced in untreated EAE mice in com- Modulation of the Th9 cell-related immune responses parison with healthy mice at post EAE induction period. The treatment Differentiation of Th9 cells Expression of IL-9 with ginger prevent body weight loss in the EAE mice (Jafarzadeh et al., Modulation of the Th22 cell-related immune responses 2014d)(Table 2). Therefore, ginger has the potentials to improve the α↓ Differentiation of Th22 cells Expression of TNF- clinical and pathological parameters in EAE mice. ↓ Expression of IL-22 Expression of IL-6 5. The possible immunomodulatory, anti-inflammatory and anti- Down-regulation of the B cell-related immune responses oxidative potentials of ginger in multiple sclerosis IgM production↓ IgG production↓ ↓ IgE production 5.1. Ginger down-regulates Th1 cell-related immune responses Modulation of the macrophages responses Differentiation of M1 macrophages↓ Expression of IL-1β↓ ff + ff ↓ α↓ The Th1 cell di erentiation from naïve CD4 T lymphocytes occurs Di erentiation of M2 macrophages Expression of TNF- γ Expression of IL-6↓ Expression of IL-12↓ after antigenic recognition in the presence of IFN- and IL-12 (Zhang Expression of iNOS↓ NO production↓ et al., 2014b). T-bet (T box expressed in T cells) is also considered as a PGE2 production↓ TXB2 production↓ Th1 cell-specific transcription factor (Schmitt and Ueno, 2015, Zhang Down-regulation of the antigen presenting cells et al., 2014b). Th1 cells trigger the cell-mediated immunity, which play Expression of CD80 (CD86)↓ Expression of the MHC class II a principle role in the protection against intracellular pathogens Expression of CD40↓ molecules↓ (Jafarzadeh et al., 2018b). However, uncontrolled Th1 cell-related re- Modulation of the production of pro- and anti-inflammatory cytokines sponse may provoke immunopathologic reactions (Schmitt and Ueno, Expression of IL-1β↓ Expression of TNF-α↓ 2015, Zhang et al., 2014b). Elevated number of Th1 cells was demon- ↓ ↓ Expression of IL-6 Expression of IL-8 strated in MS patients (Kaskow and Baecher-Allan, 2018). IL-12 may Expression of IL-33↓ Expression of IL-10↑ Expression of IL-27↑ take parts a critical role in the EAE and MS pathogenesis through the elicitation of the Th1- and Th17 cell differentiation (Lasek et al., 2014). Down-regulation of the arachidonic acid-derived mediators γ Prostaglandins production↓ Leukotrienes production↓ A powerful association was also reported between the IFN- levels and COX-1 activity↓ 5-LOX activity↓ the number of active lesions in MS patients (Kaskow and Baecher-Allan, COX-2 activity↓ 2018). IFN-γ increases the expression of the MHC molecules by re- fi Modulation of the toll-like receptors-related signaling pathways sidential and in ltrated cells within the CNS, which lead to the more + + MyD88 expression↓ TRIF expression↓ activation of the CD4 and CD8 T lymphocytes (Kaskow and Baecher- NF-κB activation↓ IKK activation↓ Allan, 2018). IFN-γ also kills the oligodendrocytes that enhance the IRF3 activation↓ TBK1 activation↓ ↓ ↓ neuronal demyelination (Kaskow and Baecher-Allan, 2018). Moreover, ERK1/2 activation MAPK activation γ AP-1 activation↓ TLR4 dimerization↓ IFN- may perform a major role in the EAE and MS pathogenesis via the IκBα expression↑ PI3K activation↓ promoting of the M1 macrophage differentiation and up-regulating the Akt activation↓ expression of inducible nitric oxide synthase (iNOS) by DCs and mac- Modulation of the inflammasome-related responses rophages (Dungan et al., 2014, Xiao et al., 2008). NLRP3 expression↓ Caspase-1 activity↓ Ginger inhibits the IL-12 synthesis by the LPS-activated macrophage IL-1β expression↓ (Tripathi et al., 2008). Ginger also diminishes the expression of the Down-regulation of the oxidative stress costimulatory molecules (such as CD80 and CD86) and MHC class II ROS production↓ iNOS expression↓ molecules by antigen-presenting cells (APCs) ((Tripathi et al., 2008). ↑ ↑ SOD expression CAT expression Therefore, ginger negatively affects the antigen presentation, T cell ↑ ↑ GPx expression GSH production γ GR expression↑ GST production↑ activation, and IFN- and IL-2 secretion by T cells ((Tripathi et al., H202 production↓ Malondialdehyde production↓ 2008). It has been found that the serum IL-12 and IFN-γ levels and the Myeloperoxidase expression↓ NO production↓ IL-12 expression in the CNS of EAE mice were higher than the normal QR expression↑ control group (Jafarzadeh et al., 2017a, Jafarzadeh et al., 2014d). Down-regulation of the expression of the chemokines and chemokines receptors Further, treatment of the EAE mice with the ginger decrease the IL-12 CCL22 expression↓ CCL20 expression↓ expression in the spinal cords and serum samples (Jafarzadeh et al., ↓ ↓ CXCL10 expression RANTES expression 2017a). The reducing influences of the ginger on the IFN-γ synthesis MCP-1 expression↓ CCR4 expression↓ were also indicated in EAE mice (Jafarzadeh et al., 2014d)(Table 2). CCR6 expression↓ Accordingly, the decreasing impacts of ginger on the IFN-γ and IL-12

Down-regulation of the adhesion molecules expression may lead to the modulation of the both Th1- and Th17 cell- ICAM-1 expression↓ VCAM-1 expression↓ related responses and finally lead to the EAE amelioration. In a mouse E-selectin expression↓ model of collagen-induced arthritis, treatment with the ginger decrease

56 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

Fig. 1. The possible immunomodulatory, anti-inflammatory and anti-oxidative potentials by which ginger and its components may contribute in the treatment of MS. the serum IFN-γ, IL-4 and IL-17 amounts and reduce the IL-17 expres- autoantibodies to myelin-associated components (Raphael et al., 2015). sion in the paw and spleen tissues (Hwang and Jung, 2017). Hence, it It has been demonstrated that the ginger extract suppresses the has been concluded that ginger has a preventive effect against RA ovalbumin (OVA)-induced allergic airway inflammation in mice progression through the suppressing of the secretion of Th1-, Th2- and through preventing the generation of the Th1- and Th2 cell-related Th17 cell-related cytokines (Hwang and Jung, 2017). Moreover, in a cytokines and inhibiting of the IgE production (Ahui et al., 2008). The model of allergic dermatitis, it was found that 6-shogaol attenuates the oral administration of the ginger to mice with OVA-induced allergic skin lesions and reduces the Th1 cell- (including IL-12, IFN-γ and TNF- rhinitis also decreases the disease scores, inhibits the mast cell ag- α) and Th2 cell- (such as (IL-4 and IL-13) type cytokines (Park et al., gregation into the nasal mucosa and suppresses the generation of the 2016). OVA-specific IgE (Kawamoto et al., 2016). In this model, 6-Gingerol Some of the ingredients of ginger including 6-, 8- and 10-gingerol also inhibits the production of the Th1- and Th2 cell cytokines in the decrease the T lymphocyte activation and expansion, and reduce the OVA-stimulated spleen cells (Kawamoto et al., 2016). 6-gingerol also IFN-γ production by in vitro stimulated T lymphocytes in a dose-de- suppresses the expansion and differentiation of both Th1- and Th2 cells pendent process (Bernard et al., 2015). 8- and 10-gingerol also suppress from naïve T lymphocytes (Kawamoto et al., 2016). The repressive the IL-2 secretion by stimulated T lymphocytes and interfere with the impacts of ginger on the Th2 cell-mediated responses were also in- IL-2 receptor signaling (Bernard et al., 2015)(Table 2). Collectively, dicated in a mouse model of OVA-induced allergic asthma (Khan et al., from the aforementioned explanations, it is concluded that ginger and 2015)(Table 2). some of its components may have the therapeutic potential for treat- The clarification of the Th2 cell action in the immunopathological ment of the certain Th1 cell-dependent autoimmune disorders such as process of MS and the evaluation of the ginger effects on this subset of T MS. cell need to be considered in more studies. If the involvement of the Th2 cells in the immunopathological process of MS is proved, then it seems 5.2. Ginger modulates the Th2 cell-related immune responses that the ginger has a powerful potential to modulate these cells.

The naïve CD4+ T lymphocytes are induced to become Th2 cells 5.3. Ginger down-regulates the Th17 cell-related immune responses following the antigen recognition in the presence of the IL-4. The Th2 cell-specific transcription factor, GATA binding protein 3 (GATA-3) The naïve CD4+ T lymphocytes are polarized to Th17 cells after stimulates the generation of the Th2 cell-linked cytokines, such as IL-4, antigen recognition in the simultaneous presence of the IL-6 and TGF-β IL-5 and IL-13 (Schmitt and Ueno, 2015, Zhang et al., 2014b). The Th2 (Rathore and Wang, 2016, Volpe et al., 2015). Th17 cells express RORγt cells stimulate B-cells to produce immunoglobulins, which providing as their major transcription factor and release various kinds of cyto- humoral immunity (Jafarzadeh et al., 2018b, Na et al., 2016). The kines, including IL-17 (IL-17A), IL-17F, IL-21, IL-22, IL-23, IL-26, TNF- development of the type I hypersensitivity reactions (such as allergic α, CCL20 and GM-CSF (Basu et al., 2013, Jafarzadeh et al., 2018b, and atopic diseases) are also associated with the Th2 cell-dependent Zhang et al., 2014a). IL-17 elicits the production of proinflammatory responses (Na et al., 2016). There are some disagreements concerning mediators such as IL-8, CXCL1, CXCL6, CCL2, IL-1β, IL-6, TNF-α, GM- the contribution of the Th2 cells in the MS pathogenesis. A negative CSF and G-CSF from different cells, in particular myeloid cells, epi- association was reported between the amounts of the IL-4 expression in thelial cells, fibroblasts, endothelial cells, and synoviocytes (Bedoya glial cells and EAE severity, suggesting that the upregulation of the Th2 et al., 2013, Jafarzadeh et al., 2018b). Th17 cells perform a critical role cells may exert limiting effects on the inflammation in EAE and MS in defence against some extracellular pathogens and are involved in the (Broberg et al., 2004, Raphael et al., 2015). On the other side, the several inflammatory and autoimmune illnesses (Bedoya et al., 2013, presence of Th2 cells was indicated in the lesions of MS patients Jafarzadeh et al., 2018b). (Raphael et al., 2015). The elevated serum IL-4 levels in the MS patients Accumulation of the both Th1- and Th17 cells into the CNS takes are also positively associated with more demyelination during the acute place during MS and EAE development (Fletcher et al., 2010, phase of disease (Raphael et al., 2015). The induction of Th2 cell-linked Jafarzadeh et al., 2018a, Raphael et al., 2015). The mice with defect in responses may exacerbate EAE by enhancing the production of either RORγt or T-bet were resistant against EAE development (Fletcher

57 .Jfrae,M Nemati M. Jafarzadeh, A. Table 2 Summary of studies on immunomodulatory properties of ginger and some of its active ingredients.

Models Host* Treatment agent Treatment doses Treatment route Treatment Results Ref. program

EAE C57bl/6 mice Ginger extract 200 and 300 mg/kg i.p 28 days - EAE clinical symptoms.↓ (Jafarzadeh et al., 2014d) - Animal body weight.↑ - Histopathological grades in the CNS.↓ - Expression of IL-33 in the CNS.↓ - Expression of IL-27 in the CNS.↑ - Serum levels of IFN-γ.↓ EAE C57bl/6 mice Ginger extract 200 and 300 mg/kg i.p 28 days - Expression of IL-23 and IL-17 in CNS.↓ (Jafarzadeh et al., 2015a) - Serum levels of IL-23 and IL-17.↓ EAE C57bl/6 mice Ginger extract 200 and 300 mg/kg i.p 28 days - Expression of IL-12 in the CNS.↓ (Jafarzadeh et al., 2017a) - Serum IL-12 levels.↓ - Expression of TGF-β in the CNS.↑ - Serum TGF-B levels.↑ Collagen-induced arthritis DBA/1J mice Ginger extract 100 and 200 mg/kg/ Orally 14 days - Levels of IL-4, IFN-γ, and IL-17 in the paw (Hwang and Jung, 2017) day tissues.↓ - Expression of MMP-1, MMP-3, and MMP-13 in the paw tissues.↓ - Bone destruction.↓ Ovalbumin (OVA)-induced NOD mice Ginger extract 360 mg/kg/day i.p 2 days - IL-4, IL-5, IFN-γ and eotaxin levels in lungs, sera (Ahui et al., 2008) allergic airway and BALF.↓ - The number of eosinophils, monocytes and neutrophils in the BALF.↓ - OVA-specific IgE.↓ OVA-induced allergic asthma Balb/c mice Ginger extract 500 and 720 mg/kg/ i.p 7 days - IL-4 and IL-5 expression in lung tissue.↓ (Khan et al., 2015) ↓ 58 day - Levels of IL-4 and IL-5 in BALF. - Level of total serum IgE.↓ - The number of eosinophils and neutrophils in the BALF.↓ - The number of eosinophils in blood.↓ - Mucus hypersecretion and goblet cells hyperplasia.↓ Cardiac allograft C57BL/6 mice Ginger extract 28, 140, and 280 mg/ Orally 10 days - TGF-β producing lymphocytes in MLC.↑ (Chumpon Wilasrusmee kg/day - IL-4 producing lymphocytes in MLC.↓ et al., 2007). - Lymphocyte proliferation in MLR.↓ - 1Allografts survival.↑ OVA-induced allergic rhinitis Balb/c mice Ginger 2% of diet Orally 42 days - Allergic rhinitis symptoms.↓ (Kawamoto et al., 2016) - The number of mast cells in the nasal mucosa.↓ - Serum levels of OVA-specific IgE.↓ Con A-stimulated Lymphocytes C57BL/6 mice Ginger extract 1, 10, 100 and 1000 In vitro 48 hours - IFN-γ and IL-2 production.↓ (Chumpon Wilasrusmee μg/ml - IL-4 production.↓ et al., 2007). Journal ofNeuroimmunology324(2018)54–75 - IL-10 production.↑ - Lymphocyte stimulation index.↓ Mesenteric lymph node Sprague Dawley rat Ginger extract 10 mg/ml In vitro 24 hours - IgM production.↓ (Kaku et al., 1997) lymphocytes - IgG production.↓ Peritoneal macrophages C57Bl/6 mice Ginger extract 1 μl/ml In vitro 1 hour - Expression of MHC class II molecule.↓ (Tripathi et al., 2008) - CD80 and CD86 expression.↓ - IL-12 production.↓ - Macrophage capacity to induce T cell activation (IL-2 and IFN-γ production).↓ - TNF-α production.↓ - IL-1β production.↓ - RANTES production.↓ - MCP production.↓ (continued on next page) A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

et al., 2010). The Th1- and Th17 cells may perform complementary This 2 functions in the EAE and MS pathogenesis (Fletcher et al., 2010). Th1

) cells induce the macrophage accumulation into the spinal cord, whereas ) Th17 cells enhance the neutrophils aggregation, in particular in the brain (Fletcher et al., 2010, Kroenke et al., 2008). The high number of the self-reactive Th17 cells were indicated in the CNS lesions in MS patients (Becher and Segal, 2011). The elevated fi

Park et al., 2016 Bernard et al., 2015 IL-17 quantities in the serum and CSF of MS patients also con rm the Ref. ( ( participation of this cytokine in the MS development (Ghaffari et al., 2017, Kostic et al., 2014). The possible mechanisms by which IL-17

and IL- contribute in the immunopathological process of MS and EAE may be ↓ through the recruitment of neutrophils into the CNS, induction of the reactive oxygen species (ROS) generation in the brain, induction of the expression of matrix metalloproteinases, stimulation of the microglia fl ↓

↓ cells to produce pro-in ammatory mediators, and the stimulation of the astrocytes to secrete chemokines (Jadidi-Niaragh and Mirshafiey, 2011, , IL-4, IL-13, IFN- γ ↓ ↓ α

↓ Mirshafiey et al., 2014). ↓ ↓ ↓ ↓ ↓ The maintenance and the full activation of the Th17 cells are sup- ↓

ect was observed using dose 280 mg/kg of ginger extract. ported by IL-23, which is essentially secreted by the DCs and macro- phages (Zuniga et al., 2013). The participation of the IL-23/IL-17 axis in uence on IL-4 production production. expression. fl

↓ fl γ γ the some in ammatory disorders such as MS and EAE was demon- This e ff 1 ↓ IL-2 production. strated (Becher and Segal, 2011, Ghaffari et al., 2017, Kostic, et al., 2 - Allergic dermatitis scores. - The expression of activation markers CD25 and 12. - The Nrf2 and HO-1 expression in skin. - Serum levels of IgE. ↓ - Serum levels of TNF- - - IFN- CD69. Results -Noin - Th2 cell polarization. - IL-10 expression. - IFN- 2014, Noack and Miossec, 2014). IL-23/IL-23R deficient mice were resistant against the EAE development (Qu et al., 2013). It has been found that the IL-17 and IL-23 expression in the spinal cords and the serum IL-17 and IL-23 levels in EAE mice was higher than healthy mice (Jafarzadeh et al., 2015a). Treatment of EAE mice with the ginger decreases the IL-17 and IL-23 expression in the spinal cords 28 days 48, 72 and 96 hours - T cell proliferation. 24 hours program 7 days - IL-4 secretion. 7 days - Th1 cell polarization. 3 days - IL-4 and IL-13 Expression. 24 h - IL-2 Expression. and reduces the serum IL-17 and IL-23 levels compared with untreated control EAE mice (Jafarzadeh et al., 2015a)(Table 2). Ginger may di- rectly and/or indirectly influence the IL-17 production. The preventive impacts of ginger and some of its derivatives on the IL-6 production have been also indicated (Ho et al., 2013). Accordingly, ginger may reduce the Th17 cell-related responses through the suppressing of the In vitro In vitro Orally In vitro In vitro In vitro In vitro IL-6 production (Jafarzadeh et al., 2015a). Within the CNS, the microglia cells can secrete cytokines such as IL- (on cells derived from human or animal sources). 23, IL-1 and TNF-α (Derkow et al., 2015). IL-1 and TNF-α also enhance M M μ μ M the polarization and activation of the Th17 cells (Jadidi-Niaragh and μ in vitro M Mirshafiey, 2011). It has been also indicated that that 6-shogaol sup- μ β α M M 50 presses the LPS-mediated iNOS, COX-2, IL-1 and TNF- expression μ μ – through the downregulation of MAPK signaling and NF-κB activation in 10 and 50 Treatment doses Treatment route Treatment 50 and 100 25 and 50 mg/kg/day 50 the microglial cells (Ha et al., 2012). Therefore, the diminishing in- fluences of the ginger or its derivatives on the IL-23, IL-1 and TNF-α production may result in the down-regulation of the IL-17 expression. It is noteworthy that IL-27 has inhibitory effects on the Th17 cell differentiation (Meka et al., 2015). Lower IL-27 expression was also indicated in the CNS of EAE mice in comparison with the healthy mice (in humans or in animals) or (Jafarzadeh et al., 2014d). Moreover, administration of the ginger to the EAE mice restore the IL-27 expression (Jafarzadeh et al., 2014d) [6]-Shogaol Treatment agent [10]-gingerol [10]-gingerol [6]-gingerol 6.5 in vivo (Table 2). Therefore, the decreasing effects of the ginger on the IL-17 expression may also perform in part via the enhancing of the IL-27 production, which in turn suppresses the Th17 cell differentiation. Collectively, the decreasing impacts of ginger and some of its compo- nents on the Th17 cell-related responses may provide a basis for pos- sible their therapeutic potentials for treatment of MS. C57BL/6 mice [6]-gingerol [8]-gingerol C57BL/6 mice [6]-gingerol [8]-gingerol ICR mice Host* c mice 5.4. Ginger up-regulates the Treg cell-related immune responses

Treg cells perform a principle role in the establishing of the per- ipheral self-tolerance. The suppressive influences of the Treg cells are ) exerted mainly through the secretion of immunosuppressive cytokines TGF-β, IL-10 and IL-35 (Jafarzadeh et al., 2018b, Rodriguez-Perea

continued et al., 2016). The transcription factor FOXP3 is expressed by Treg cells ( and mutations in the foxp3 gene result in the development of the serious autoimmune disorders (Etesam et al., 2016, Nie et al., 2015). ect was observed using [8]-gingerol and [10]-gingerol. T- lymphocytes T- lymphocytes Allergic dermatitis Models Spleen cells OVA-sensitized Balb/ Human T- cell line Jurkat cells Human [6]-gingerol 50 Spleen cells Balb/c mice [6]-gingerol 12.5 and 25 Table 2 *Host represents that the experiments were performed e ff The adoptive transfer of the Treg lymphocytes confer protection

59 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75 against EAE, which is associated with the modulation of the Th1- and indicated in EAE mice (Jafarzadeh et al., 2014d). Therefore, it is ex- Th2 cell-linked responses and low lymphocyte accumulation in the CNS pectable that ginger may have modulatory effects on the Th9 cell-re- (Wang et al., 2006). Some defects were reported in the number or lated responses. functions of Treg cells in the MS patients and EAE models (Buc, 2013, Raphael et al., 2015). However, it has been indicated that there was no 5.6. Ginger may down-regulate Th22 cell-related immune responses meaningful difference between MS patients and healthy individuals with respect to the serum concentrations of IL-35 as a Treg cell-related The IL-22 producing Th22 cells are polarized from naïve T lym- cytokine (Jafarzadeh et al., 2014c). It has been also demonstrated that phocytes by simultaneous presence of TNF-α and IL-6 (Fujita et al., the effector T cells separated from the MS patients are non-responsive 2009, Jia and Wu, 2014a). The frequency and the response of the Th22 to the Treg cell-mediated suppression (Kaskow and Baecher-Allan, cells are increased during the relapse phases of the MS disease (Fard 2018). et al., 2016). An association has been also shown between the Th22- TGF-β, a powerful immunoregulatory cytokine, is mainly produced and Th17 cells, indicating that both subsets may perform a synergistic by Treg cells and has protective impacts against EAE and MS devel- contribution in the MS progression (Fard et al., 2016). The impacts of opment (Mirshafiey and Mohsenzadegan, 2009). Administration of ginger on the Th22 cell activity have not been investigated, yet. How- anti-TGF-β antibody to the EAE mice exacerbates the disease severity, ever, the lessening effects of ginger on the TNF-α and IL-6 (main in- while treatment with TGF-β prevents disease (Mantel and Schmidt- ducers of Th22 cells) were indicated (Ho et al., 2013, Mahluji et al., Weber, 2011). Lower serum TGF-β concentrations were also indicated 2013, Zehsaz et al., 2014). Therefore, it is expectable that ginger may in the developmental stage of EAE (Lu et al., 2014). have modulatory effects on the Th22 cell-related responses. TGF-β is essential for differentiation of the both Th17- and Treg cell Together, the ginger or its major components may directly affect the subsets. The stimulation of naïve CD4+ T lymphocytes in the existence differentiation and the activity of Th1-, Th2-, Th17-, Th9-, Th22- and of TGF-β cause Treg cell differentiation, while, simultaneous presence Treg cells presumably through interfering with specific cellular signal of TGF-β and IL-6 results in the Th17 cell development (Zhang et al., transduction pathways like transcription factors. It is well known that 2014a). A diversion in the Th17/Treg cell balance with tendency to- 6-gingerol inhibits the differentiation of Th1 cells in a strong Th1 cell- ward Th17 cell response may contribute in the EAE and MS develop- polarizing condition (presence of IL-2/IL-12 and anti-IL-4 neutralizing ment (Raphael et al., 2015). antibody) (Kawamoto et al., 2016). Similarly, 6-gingerol prevents the It has been found that the administration of the ginger to the EAE differentiation of Th2 cells in a powerful Th2 cell-polarizing situation mice increases the serum TGF-β levels and enhances the TGF-β ex- (presence IL-4 and anti-IL-12 neutralizing antibody) (Kawamoto et al., pression in the CNS (Jafarzadeh et al., 2017a)(Table 2). On the other 2016). Hence, the inhibition of the of Th1 cell differentiation by 6- side, the preventive impacts of the ginger and some of its ingredients on gingerol is not due not to the enhancement of Th2 cell-related cyto- the IL-6 production have also demonstrated (Ho et al., 2013, Lee et al., kines. It has been suggested that 6-gingerol may directly affects the 2012). Therefore, the administration of ginger to the EAE mice may TCR-mediated signal transduction pathways (Kawamoto et al., 2016). improve the Th17/Treg cell imbalance with a tendency toward the Treg The direct effects of ginger or its major ingredients on the Th1-, Th2-, cells that may contribute a principle role in the attenuation of EAE. Th17-, Th9-, Th22- and Treg cells remain to be described in future Experimentally, in a mouse model of cardiac allograft, it has been studies. The ginger or its major component may also indirectly interfere revealed that ginger extract reduces lymphocyte expansion, decreases with differentiation, activation and expansions of the Th1-, Th2-, Th17-, the generation of the IL-2, IL-4 and IFN-γ and increases the production Th9-, Th22- and Treg cells through interfering in the cytokine network. of the Treg cell-related immunosuppressive cytokines including IL-10 The counting of the aforementioned effector T cells in the circulating or and TGF-β (Chumpon Wilasrusmee et al., 2007)(Table 2). tissue specimens obtained from ginger-treated animals or humans using their specific cellular markers may fill this knowledge gap. In addition, 5.5. Ginger may down-regulate the Th9 cell-related immune responses the in vitro stimulation of the peripheral blood mononuclear cells (PBMC) in the presence of ginger or its constituents and then the The IL-9 producing Th9 cells are polarized from naïve T lympho- measurement of the effector T cells-related parameters may clarify their cytes by simultaneous presence of the IL-4 and TGF-β (Jia and Wu, effects. 2014b, Wilhelm et al., 2011). In addition, IL-1, IL-21, IL-25 and IL-23 enhance the IL-9 production, while IL-27 suppresses it (Jia and Wu, 5.7. Ginger down-regulates the B cell-related immune responses 2014b, Wilhelm et al., 2011). As mentioned for Th2 cells, there are disagreements regarding the contribution of the Th9 cells in the MS There are evidences supporting the participation of the B cells in the pathogenesis. The IL-9 receptor is highly expressed in residential cells MS pathogenesis, such as the presence of the oligoclonal bands (OCBs) of the CNS, such as astrocytes, microglia cells, oligodendrocytes and in the CSF of more than 90% of the MS patients, determination of the oligodendrocyte progenitor cells, and its expression is enhanced during various types of the myelin-related autoantigens as the targets of au- EAE development (Deng et al., 2017). In addition, IL-9 induces astro- toantibodies, clonal proliferation of the B cells in the CSF and periph- cytes to produce chemokines such as CXCL9 and CCL20 (which at- eral tissues, deposition of immunoglobulins and complement in the MS tracting leukocytes, especially, neutrophils and monocytes, to the in- lesions, and the appearance of the B cell follicle-like compartments in flammatory sites) and express matrix metalloproteinases such as MMP3 the CNS of the MS patients (Fraussen et al., 2016, Probstel et al., 2015). (Ding et al., 2015). IL-9-mediated CCL20 expression causes the migra- Moreover, the expression of BAFF and CXCL13 was indicated in the CSF tion of the Th17 cells into the CNS during EAE progression, so that IL-9- and lesions of MS patients that act as powerful chemo-attractants for B and IL-9R deficient mice exhibit low Th17 cell accumulation in the CNS cells (Probstel et al., 2015). In addition, B cells are involved in the MS and display mild type of EAE (Deng et al., 2017, Zhou et al., 2011). pathogenesis through the secretion of pro-inflammatory cytokines, in- Moreover, neutralization of IL-9 using monoclonal antibodies sup- cluding TNF-α and IL-6 (Fraussen et al., 2016, Probstel et al., 2015). presses the IL-17 production, representing that IL-9 may consider as a The direct impacts of the ginger on the B cell activation and antibody suitable target for prevention of Th17 cell activation in the EAE (Li synthesis have not been investigated, adequately. Experimentally, it has et al., 2010). The IL-27 also abolish the encephalitogenicity of the Th9 been indicated that the ginger suppresses the IgG and IgM production cells in the EAE disease (Deng et al., 2017). by lymphocytes isolated from rat mesenteric lymph nodes (Kaku et al., The ginger influence on the Th9 cell activity has not been in- 1997)(Table 2). vestigated, yet. As mentioned IL-27 inhibits Th9 cells. On the other side, Ginger and its constituents may directly and/or indirectly influence the enhancing effects of ginger on the IL-27 production have been the antibody production. As B cell activation and expansion, and their

60 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75 differentiation to antibody-secreting cells require the help from Th 2014). cells, therefore, the reducing influence of the ginger or its derivatives on Collectively, ginger and its constituents may reduce the powerful the Th cells and APCs lead to the down-regulation of antibody synth- detrimental effects of macrophages/microglia during MS. The impact of esis. Moreover, ginger and its constituents may directly affect the B ginger and its active derivative on the beneficial effects of macro- cells. The influences of the ginger and its active components on the phages/microglia such as promotion of the M2 polarization using spe- expression of the B-cell antigenic receptor, B-cell activation, B-cell re- cific cellular markers need more consideration. lated signaling pathways, B-cell expansion and differentiation need to be clarified in future investigations. 5.9. Ginger modulates the production of the pro- and anti-inflammatory cytokines 5.8. Ginger modulates the macrophages responses Elevated levels of the pro-inflammatory cytokines (such as IL-1β, IL- The classical or M1 macrophages produce pro-inflammatory med- 6, IL-23, IL-33, TNF-α and IL-17) and diminished levels of the anti- iators such as IL-1β, IL-12, IL-18, IL-23, TNF-α, ROS and NO (Edholm inflammatory cytokines (including IL-10, IL-27 and TGF-β) were in- et al., 2017). The alternative or M2 macrophages are very phagocytic dicated in MS patients and EAE mice (Ghaffari et al., 2017, Hasheminia and secrete anti-inflammatory and immunosuppressive cytokines, in- et al., 2015, Jafarzadeh et al., 2017a, Jafarzadeh et al., 2015a, cluding TGF-β and IL-10 (Edholm et al., 2017). M1 macrophages me- Jafarzadeh et al., 2014d)(Chu et al., 2018, Jafarzadeh et al., 2016). The tabolize L-arginine to L-citruline and NO through the expression of dysregulation in the cytokine production may contribute to the MS iNOS, whereas M2 macrophages express arginase that metabolize L- pathogenesis. arginine to L-ornithine, which is a precursor molecule for polyamines It was demonstrated that the ginger supplementation have reducing and proline components of the collagen, a key element in the tissue effects on the circulating levels of IL-1, IL-6 and TNF-α in patients with repair (Edholm et al., 2017). The classical M1 macrophages are largely knee osteoarthritis (Mozaffari-Khosravi et al., 2016) and in men en- induced by Th1 cell cytokines such as IFN-γ, whereas M2 macrophages durance runners (Zehsaz et al., 2014). Moreover, the oral administra- are differentiated by Th2 cell cytokines such as IL-4 and IL-13 tion of the ginger to the type 2 diabetes patients reduces the serum (Moghaddam et al., 2018). The M1/M2 macrophage polarization de- concentrations of IL-6 and TNF-α and an inflammatory parameter C- termines the tissue repair or tissue damage during inflammation reactive protein (Mahluji et al., 2013)(Table 3). In experimental animal (Moghaddam et al., 2018). The M1 macrophages amplify the in- models of diabetic nephropathy, it was found that the treatment with flammatory reactions that lead to the tissue damage, while M2 mac- zingerone improves the renal functions, prevent the NF-кB activation, rophages inhibit the inflammation and participate in the tissue repair, reduce the subsequent expression of TNF-α, IL-6 and IL-1β, and abolish remodeling and vasculogenesis (Edholm et al., 2017, Moghaddam et al., the ROS production (Cui et al., 2018, Rehman et al., 2018)(Table 3). 2018). Moreover, treatment with zerumbone reduces the plasma and spinal In the initial stages of MS, macrophages and microglia acquire in- levels of IL-1β, IL-6, and TNF-α (but not IL-10) in a mouse model of flammatory properties and display the M1 phenotype, which promote neuropathic pain (Gopalsamy et al., 2017). Further, in a cellular model neuroinflammation in the CNS (Chu et al., 2018, Yadav et al., 2015). of gut inflammation, it was observed that ginger and some of its com- Moreover, macrophages in the active MS lesions mainly exhibit the M1 ponents, including 6-gingerol and 6-shogaol suppress the iNOS, IL-6, type properties, however, a main subgroup of macrophages display an and IL-8 expression through the NF-κB suppression (Kim et al., 2017). intermediate status (Vogel et al., 2013). Further, the deviation of Moreover, 6-, 8-, and 10-gingerol attenuate the colitis symptoms and macrophages in the direction of pro-inflammatory or im- reduce the serum levels of IL-1β, IL-6, and TNF-α in an animal model of munomodulatory phenotypes at the early clinical phase is a determi- ulcerative colitis (Zhang et al., 2017)(Table 3). native parameter for the development of a mild or a serious EAE disease IL-33 is constitutively expressed in the endothelial cells and epi- (Mikita et al., 2011). The M2 macrophage-related responses are in- thelial barriers, however, the highest expression of this cytokine are hibited during the relapsing EAE, and the curative administration of the observed in the CNS of mice (Schmitz et al., 2005). The elevated IL-33 M2 type of monocytes inhibits the development of the relapsing EAE levels were indicated in the periphery and CNS of MS patients and EAE (Mikita et al., 2011). It seems that the M2 macrophages perform an mice (Christophi et al., 2012, Jafarzadeh et al., 2016, Jafarzadeh et al., essential role in the remission process by eliminating the myelin debris 2014d, Schmitz et al., 2005). IL-33 may involve in the EAE and MS and directing the oligodendrocyte differentiation during remyelination. diseases through the driving of the Th1- and Th17 cell responses Therefore, a change from M1- toward M2 type microglia/macrophages (Jafarzadeh et al., 2014d, Milovanovic et al., 2012). The raised IL-33 may induce remyelination (Miron et al., 2013, Yadav et al., 2015). expression was indicated in the spinal cord samples obtained from the Although, the exact effects of the ginger on the M1- and M2 type EAE mice (Jafarzadeh et al., 2014d). The administration of the ginger to macrophages remain to be clarified in future investigations, however, the EAE mice reduces the IL-33 expression in the spinal cords the inhibitory impacts of the ginger and its efficient components on the (Jafarzadeh et al., 2014d)(Table 2). The EAE attenuation using neu- expression of M1 macrophages-related parameters such as iNOS, NO tralizing anti-IL-33 antibodies was attributed to the reduction in the and pro-inflammatory cytokines including IL-1, IL-6, IL-12 and TNF-α IFN-γ and IL-17 production and enhancement of the IL-10 and TGF-β have been well documented (Ho et al., 2013, Huang et al., 2014). expression in the CNS of EAE mice (Li et al., 2012). Accordingly, the Ginger also inhibits the generation of a number of pro-inflammatory attenuating impacts of ginger on the IL-33 production may modulate cytokines (such as IL-12, TNF-α, IL-1β) and pro-inflammatory chemo- Th1- and Th17 cell responses and enhance the Treg cell activities that in kines (such as RANTES, MCP-1) in the LPS-induced macrophages turn ameliorate autoimmunity. (Tripathi et al., 2008). The shogaols (6-, 8- and 10-shogaol) and the Another cytokine, IL-27 have anti-inflammatory effects so that IL- gingerols (8- and 10-gingerol) suppress the expression of the neurotoxic 27R-deficient mice develop extreme pathological Th1- and Th2 cell- and proinflammatory mediators such as NO, TNF-α, IL-1β and IL-6 by relate responses (Stumhofer and Hunter, 2008). Interestingly, the mice LPS-stimulated microglia through the downregulation of the NF-κB lacking the IL-27R are more vulnerable to EAE and have a higher fre- activation (Ho et al., 2013). In a mouse model of fibromyalgia, the quency of Th17 cells than wild ones in their lesions (Batten et al., ginger supplementation decreases the synthesis of the some pro-in- 2006). The blockade of the binding of IL-27 to its receptor also causes flammatory mediators such as IL-1β, NO, PGE2 and TXB2 in the LPS- more serious EAE development (Stumhofer et al., 2006). It has been induced macrophages (Montserrat-de la Paz et al., 2018). Moreover, 6- shown that IL-27 expression was down-regulated in the CNS of EAE Dehydrogingerdione reduces the expression of the IL-1β, IL-6, TNF-α mice and injection of the ginger to the EAE mice enhances the IL-27 and NOS in the LPS-stimulated murine macrophages (Huang et al., expression in the spinal cords (Jafarzadeh et al., 2014d)(Table 2).

61 .Jfrae,M Nemati M. Jafarzadeh, A. Table 3 Summary of studies on anti-inflammatory and anti-oxidative properties of ginger and some of its active ingredients.

Models Host* Treatment agent Treatment doses Treatment Treatment program Results Ref. route

Knee osteoarthritis Human Ginger powder 500 mg/day Orally 3 months - Serum TNF-α levels.↓ (Mozaffari-Khosravi - Serum IL-1β levels.↓ et al., 2016) Endurance runners Human Ginger powder 500 mg (3 times/day) Orally 6 weeks - Plasma IL-6 levels.↓ (Zehsaz et al., 2014) - Plasma IL-1β levels.↓ - Plasma TNF-α levels.↓ Type 2 Diabetes Human Ginger tablet 1 g/day Orally 2 months - Serum TNF-α levels.↓ (Mahluji et al., 2013) - Serum IL-6 levels.↓ - Serum hs-CRP levels.↓ EAE C57bl/6 mice Ginger extract 200 and 300 mg/kg/ i.p 28 days - Expression of CCL20 and CCL22 in the (Jafarzadeh et al., day CNS.↓ 2017b) - Expression of CCR4 and CCR6 in the CNS.↓ Neurotoxicity Wistar rats Ginger extract 500 mg/kg/day Orally 2 months - Histological changes and (Hussein et al., 2017) neurodegeneration.↓ - β-amyloid accumulation in the brain.↓ - Lipid peroxidation in the brain.↓ - MDA levels in the brain.↓ - Brain GSH levels.↑ - NO levels in the brain.↓ - SOD and CAT activity in the brain.↑ - Oxidative stress in the brain.↓ - 1Ginger express free radical-, hydroxyl radical- and NO scavenging activities. ↓ 62 Diabetes-mediated brain damage Albino rats Ginger extract 500 mg/kg/day Orally 4, 6, and 8 weeks - Blood glucose levels. (El-Akabawy and El- - Histological changes in the brain.↓ Kholy, 2014) - TNF-α expression in the frontal cortex and hippocampus.↓ - iNOS expression in the frontal cortex and hippocampus.↓ -Caspase-3 expression in the frontal cortex and hippocampus.↓ - Frequency of apoptotic cells in the frontal cortex and hippocampus.↓ Hepatic oxidative stress Albino rats Ginger extract 350 mg/kg (4 dose Orally 6 weeks - Liver dysfunction.↓ (Mohamed et al., 2016) weekly) - Liver expression of CAT, SOD, GSH, and GSH-Px.↑ - Liver MDA levels.↓ Neuro-inflammation C57Bl mice [6]-Shogaol 5 or 10 mg/kg/day Orally 3 days - Microglial activation in brain cortex.↓ (Ha et al., 2012) - Microglial activation in hippocampus.↓ Journal ofNeuroimmunology324(2018)54–75 - Neuronal cell death.↓ - Production of IL-1β and TNF-α in the hippocampus.↓ Intestinal injury Sprague-Dawley rats [6]-gingerol 25 or 50 mg/kg/day Orally 3 days - Intestinal histopathological scores.↓ (Li et al., 2017) - Intestinal epithelium integrity.↑ - Intestinal SOD, GSH, and GSH-Px levels.↑ - Intestinal MDA levels.↓ - Intestinal iNOS expression and NO production.↓ - Intestinal MMP-9 expression.↓ - Intestinal MAPK, IKKα/β,IκBα and NF-κB activity expression.↓ Ulcerative colitis Sprague–Dawley rats 30 mg/kg/day i.p 7 days - Histopathological scores in colonic (Zhang et al., 2017) tissue.↓ (continued on next page) .Jfrae,M Nemati M. Jafarzadeh, A. Table 3 (continued)

Models Host* Treatment agent Treatment doses Treatment Treatment program Results Ref. route

[6]-Gingerol - MDA levels in colonic tissue.↓ [8]-Gingerol - MPO activity in colonic tissue.↓ [10]-Gingerol - SOD activity in colonic tissue.↑ - Serum IL-6, IL-1β and TNF-α levels.↓ Oxidative damage in Wistar rats [6]-Gingerol- 50 or 100 Orally 35 days - Body weight loss.↓ (Abolaji et al., 2017) brain, ovary and uterus rich fraction mg/kg/day - MPO expression.↓ - MDA, H2O2 and NO levels.↓ - CAT and SOD activities.↑ - GSH level.↑ - Caspase-3 and TNF-α expression.↓ Acute kidney injury C57BL/6 mice Zingerone 10, 20 and 40 mg/kg i.p 1 hour after injury induction - Kidney histopathologic changes.↓ (Song et al., 2016) - Renal function.↑ - TNF-α, IL-6, and IL-1β expressions in serum and kidney tissue.↓ - NF-κB activation in kidney tissue.↓ -IκBα degradation in kidney tissue.↓ - TLR4, MyD88, and TRIF expression in kidney tissue.↓ Liver damage C57BL/6 mice Zingerone 0.18, 0.36 and i.v 12 hours after injury induction - Mortality rate.↓ (Lee et al., 2018) 0.72 mg/kg - Liver histopathologic changes.↓ - Liver function.↑ - TLR4 expression in liver tissue.↓ - 2Expression of MyD88, MAPK, ERK, JNK and NF-κB in liver tissue.↓ 2 63 - IκBα level in liver tissue.↑ - 2TRIF expression in liver tissue.↓ - 2IRF3 phosphorylation in liver tissue.↓ - 2Serum IFN-β, TNF-α and IL-6 levels.↓ Diabetic nephropathy db/db mice Zingerone 50 mg/kg/day i.p 10 weeks - TNF-ɑ and IL-6 Expression in kidney.↓ (Cui et al., 2018) - NOX4 expression in kidney.↓ - Renal MDA level.↓ - ROS levels in kidney tubular cells.↓ - GSH levels in kidney tubular cells.↑ - Progression of diabetic nephropathy.↓ - Glucose-induced cytotoxicity in kidney tubular cells.↓ Cecal ligation and puncture-induced C57BL/6 mice Zingerone 0.36 or 0.72 mg/kg i.v 12 and 50 hours after injury - Histopathologic changes.↓ (Lee et al., 2017) sepsis - Liver, renal and endocrine dysfunction.↓ - Serum HMGB1 levels.↓ - Vascular permeability.↓ Journal ofNeuroimmunology324(2018)54–75 - Leukocyte migration.↓ Ovarian and Uterine toxicity Wistar rats Zingerone 25 and 50 mg/kg/day Orally 7 days - Histological changes in (Kaygusuzoglu et al., ovarian and uterine.↓ 2018) - Sex hormone imbalances.↓ - Level of SOD, CAT and GPx in ovarian and uterine.↑ - GSH levels in ovarian and uterine.↑ - MDA levels in ovarian and uterine.↓ - Levels of NF-κB, TNF-α, IL-1β and in ovarian and uterine.↓ - Levels of COX-2 and iNOS in ovarian and uterine.↓ - DNA oxidation in ovarian and uterine.↓ (continued on next page) .Jfrae,M Nemati M. Jafarzadeh, A. Table 3 (continued)

Models Host* Treatment agent Treatment doses Treatment Treatment program Results Ref. route

- Caspase-3 expression and apoptosis in ovarian and uterine.↓ Age-related inflammation Fischer rats Zingerone 2 or 8 mg/kg/day Orally 10 days - ROS production.↓ (Kim et al., 2010) - Thiol contents.↑ - NF-κB activation.↓ - NIK and IKK activation.↓ - MAPK activation.↓ - COX-2 and iNOS expression.↓ Neuro-inflammation ICR mice [6]-Paradol 1, 5, or 10 mg/kg Orally Immediately after injury - Brain damage.↓ (Gaire et al., 2015) - Neurological score.↑ - Survival of neural cells.↑ - Neural cell death.↓ - Microglial activation.↓ - Microglial proliferation.↓ - iNOS and TNF-α expression in the brain.↓ Skin tumor ICR mice [6]-Paradol 2.5 μmol Topical One week after tumor - Skin tumor growth.↓ (Chung et al., 2001) induction and 30 min before -H2O2 production in the skin.↓ tumor promotion - MPO activity in the skin.↓ - Ornithine decarboxylase activity in the skin.↓ - 3Oxidized DNA base formation.↓ Colonic epithelial cell line Human Ginger extract 425, 50, or 100 μg/mL In vitro 48 hours - IL-6, and IL-8 production.↓ (Kim et al., 2017) [6]-Gingerol (0.25, 0.5, or 1 μg/mL) - NF-κB activity.↓ [6]-Shogaol - iNOS expression.↓

64 - NO production.↓ - COX-2 expression.↓ - PGE2 production.↓ Microglial cell Sprague Dawley rats [6]-Shogaol 5 or 10 μM In vitro 24 hours - Production of IL-1β and TNF-α.↓ (Ha et al., 2012) - NO production.↓ - PGE2 production.↓ - COX-2 expression.↓ - NF-kB activity.↓ - IkB levels.↑ - MAPK phosphorylation.↓ A macrophage cell line BALB/c mice [6]-Shogaol 6 and 10 μM In vitro 12 hours - iNOS and COX-2 gene expression.↓ (Pan et al., 2008) - 5NO production.↓ - PGE2 production.↓ - IKK activation↓ -IκBα phosphorylation and degradation.↓ - NF-kB level and activation.↓ Journal ofNeuroimmunology324(2018)54–75 - ERK1/2 activation.↓ - MAPK phosphorylation.↓ - PI3K activity.↓ - Akt activity.↓ A macrophage cell line BALB/c mice [6]-Shogaol 20 and 30 μM In vitro 8 hours - NF-kB activation induced by TLR3 and (Park et al., 2009) TLR4 agonist.↓ - COX-2 expression.↓ - TBK-1 activation.↓ - IFN-β expression.↓ - TRIF-dependent signaling pathway.↓ - IRF-3 activation.↓ A chondrocytes cell line C3H/He mice [6]-Shogaol 5 μM In vitro 24 hours - IL-6 and MCP‐1 expression.↓ (Villalvilla et al., 2014) - NOS2 expression.↓ - MMP2 and MMP9 activity.↓ (continued on next page) .Jfrae,M Nemati M. Jafarzadeh, A. Table 3 (continued)

Models Host* Treatment agent Treatment doses Treatment Treatment program Results Ref. route

- ERK1/2 activation.↓ - MyD88 expression.↓ Keratinocytes Human [6]-Shogaol 5 and 10 μM In vitro 1 hour - 6Expression levels of GSH and NQO1.↑ (Park et al., 2016) - ROS generation.↓ - Expression of the Nrf2 - Expression of pERK.↓ - Expression of MAPK.↓ - Expression of pJNK.↓ Astrocytes Sprague–Dawley rats [6]-Shogaol 10 μM In vitro 24 hours - LPS-induced cell death.↓ (Shim et al., 2011) - IL-1β and IL-6 production.↓ - iNOS and COX-2 production.↓ - NF-kB activation.↓ - HSP70 expression.↑ - Histone deacetylase expression.↓ - Histone H3 acetylation.↑ H2O2-treated astrocytes Sprague–Dawley rats [6]‐shogaol 10μM In vitro 24 hours - Cell viability.↑ (Kim and Kwon, 2013) - Apoptosis rate.↓ - ROS production.↓ - Expression of Bax and caspase‐3.↓ - Production neuronal growth factors such as NGF, GDNF, and BDNF.↑ A macrophage cell line BALB/c mice [6]-Shogaol 10 or 20 μM In vitro 5 hours. - TNF-α secretion.↓ (Ho and Chang, 2018). [8]-Shogaol -Inflammasome-mediated IL-1β secretion.↓ - NLRP3 inflammasome expression.

65 - Pro-caspase-1 level.↓ - Active caspase-1 level.↓ A macrophage cell line BALB/c mice [6]-Gingerol 40 or 80 μM In vitro 12 hours - TNF-α production.↓ (Lee et al., 2009) - iNOS mRNA and protein expression.↓ -IκBα phosphorylation.↓ - NF-kB activation.↓ - PKC activation.↓ Jurkat T cell line Human [6]-Gingerol 50 μM In vitro 2 h - NF-κB activation.↓ (Kawamoto et al., 2016 - AP1 activation.↓ - Phosphorylation of all MAPKs.↓ Umbilical vein endothelial cells Human Zingerone 10, 25 and 50 μM In vitro 6 hour - LPS-induced secretion of HMGB1.↓ (Lee et al., 2017) - Expression of TLR2, TLR4 and SIRT1.↓ - Intercellular gaps as a vascular permeability indicator.↓ - NF-kβ and MAPK activity.↓ - Expression of ICAM-1, VCAM-1 and E- Journal ofNeuroimmunology324(2018)54–75 selectin.↓ - Adherence of neutrophils to umbilical vein endothelial cells.↓ - TNF-α and IL-6 production. - ERK1/2 expression.↓ A microglial cell line C57BL/6 [6]-Paradol 1, 5, 10, or 20 μg/ml In vitro 24 hours - Cell viability↑ (Gaire et al., 2015) - iNOS expression.↓ - TNF-α and IL-6 production.↓ - NO production.↓ Macrophages C57BL/6 or C3H/HeJ 1-Dehydro-[10]- 10 or 30 μM In vitro 30 min-120 min. - 7Catalytic activity of IKKβ.↓ Lee et al., 2012) mice gingerdione - TLR2, TLR4, TLR5 or TNF-α-induced IκBα phosphorylation.↓ - NF-kβ activation.↓ - AP-1 activation.↓ (continued on next page) A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

Collectively, the development of the inflammatory disorders like MS is strongly associated with an imbalance of the cytokine network. The ) results from in vitro and in vivo studies presented here clearly indicated

g/mL doses, ffi μ that that ginger and its e cient components down-regulate the pro- duction of the pro-inflammatory cytokines, which attenuates the in- flammatory response and therefore may reduce the severity of in-

Park et al., 2012 flammatory disorders such as MS. Ref. ( ↓ 5.10. Ginger down-regulates the production of the arachidonic acid-derived ↓ ↓ inflammatory mediators ↓ ↓ ↓ ↓

↓ The main constituents of ginger such as gingerols and shogaols also ects were observed using doses 0.72 mg/ activation. B

κ inhibit the prostaglandin and leukotriene producing enzymes (Grzanna or IP-10 expression. NF- β

degradation. et al., 2005). The cytosolic phospholipase A2 (cPLA2) that provide α ↓ These e ff

B arachidonic acid for the prostaglandins (PGs) and leukotrienes (LTs) 2 κ , IFN- ff β production, through the a ecting on the membrane phospholipids, is Ginger extract was used in 25, 50, or 100 4 This activity measured by pretreatment by incubation of largely expressed in EAE-related CNS lesions (Kalyvas and David, 2004, 8 , IL-1

α Marusic et al., 2008). The cPLA2α performs a critical role in the EAE The expression of NQO1 measured at 4 hours after treatment. LPS binding to MD-2 of TLR4.

6 ff

8 development through the promoting of the di erentiation of naive T Results - - IL-6 production. - iNOS or COX-2 expression. - NO and PGE2 production. - MyD88-dependent - TRIF-dependent IRF3 activation. - TNF- - MyD88-dependent AP1 activation. - LPS-induced I

The free radical-, hydroxyl radical- and NO scavenging activities α fi

1 cells toward the Th1 cells and cPLA2 -de cient mice were protected against the EAE development (Marusic et al., 2005). The suppression of cPLA2 results in the considerable reduction in the EAE development (Kalyvas and David, 2004, Marusic et al., 2008). The blockade of the cPLA2α during the effector stage of EAE was more efficient in the at- M of [6]-shogaol.

μ tenuating of the EAE severity than the blockade of each of the sub- sequent enzymes including COX-1/2 and 5-lipooxygenase (5-LOX) (Thakker et al., 2011). The cPLA2α suppressors act on the APCs to and incubated for 4 hours at 37°C. fi ff 2 diminish their capability to stimulate the antigen-speci ce ector T cell O 20 hours. Treatment program 2 expansion and to induce Th1- and Th17 cell-related cytokines secretion (Marusic et al., 2005, Thakker et al., 2011). Furthermore, the cPLA2α inhibitors may prevent the activation of the CNS-resident microglia and may enhance the oligodendrocyte survival (Thakker et al., 2011). PGs have various immunologic and inflammatory properties that In vitro route originate from the arachidonic acid through the cyclooxygenase (COX) pathway (Mirshafiey and Jadidi-Niaragh, 2010b, Palumbo and Bosetti, (on cells derived from human or animal sources).

M) in the presence of H 2013). The raised quantities of the PGs in the CSF of MS patients has μ been regarded as an important indicator of the participation of these M μ in vitro mediators in the MS pathogenesis (Mirshafi ey and Jadidi-Niaragh, 2010b). Although, the COX-1 is constitutively expressed by several

ect was observed using doses 1.5, 3, 6, 10 and 20 types of leukocytes, the COX-2 expression is induced during in- c indicators and then incubated at 25 °C for 30 min, 2 hours or 5 hours, respectively. 3, 10 or 30 flammation and acts as the main inducer of the PGE2 production fi (Palumbo and Bosetti, 2013). The COX-2 expression is highly induced This e ff 5 in oligodendrocytes and leukocytes during the demyelination processes protein with 1-Dehydro-[10]-gingerdione for 30 min and then reaction with substrate. (Carlson et al., 2010, Palumbo and Bosetti, 2013). Further, COX-2 is β M of 1-Dehydro-[10]-gingerdione. μ largely expressed by inflammatory cells, such as macrophages and mi- croglia in the active demyelinating lesions (Palumbo and Bosetti, g/mL doses. g/mL) with speci μ μ (in humans or in animals) or 2013). COX-2 can be an important target in MS therapy (Skarke et al., 1-Dehydro-[10]- Treatment agent Treatment doses Treatment gingerdione 2007). The blocking of the COX-1/2 delay the appearance of the EAE 1000 –

in vivo symptoms and decrease the disease severity, and also diminish the production of the Th1 cell-related cytokines (Marusic et al., 2008, Xiang et al., 2007). The suppressive impacts of the ginger and some of its components, including 6-gingerol and 6-shogaol on the COX-2 activity and PGE2 production have been demonstrated in a model of gut inflammation BALB/c mice Host* (Kim et al., 2017)(Table 3). Further, the suppressive effects of the 6- shogaol on the COX-2 expression and PGE2 production were demon- strated in the LPS-exposed microglia (Ha et al., 2012)(Table 3). Gin- gerols, dehydrogingerdione and 8-paradol also decrease the COX-2 expression in the LPS-stimulated macrophages (Al-Nahain et al., 2014, Nurtjahja-Tjendraputra et al., 2003). Moreover, the blocking effect of ) This activity measured by mixing certain amount of DNA with [6]-paradol (100

3 the 8-shogaol, 10-shogaol and 10-gingerol on the COX-2 activity was demonstrated (van Breemen et al., 2011).

continued In the lipooxygenase pathway, the arachidonic acid is converted to ( the different kinds of LTs (Yoshikawa et al., 2011). The 5-LOX is con- sidered as the major enzyme for synthesis of the LTs, including LTB4, Models A macrophage cell line This activity measured by pretreatment of the macrophage-derived IKK Table 3 *Host represents that the experiments were performed 7 while [6]-gingerol and [6]-shogaol were used in 0.25, 0.5, or 1 the LPS with either MD-2 or LBP for 2 h in the presence of 10 or 30 measured by mixing various concentrations of ginger (50 kg of zingerone. LTC4, LTD4 and LTE4 (Yoshikawa et al., 2011). The raised amounts of

66 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

LTs, in particular LTB4 were indicated in the CSF of MS patients dependent signaling leads to the expression of type I IFNs via the (Mirshafiey and Jadidi-Niaragh, 2010a). IRAK1-induced IRF7 activation (De Nardo, 2015). It has been found that the 5-LOX pathway involves in the neuroin- TLR3 can directly interact with TRIF, whereas TLR4 (that utilizes flammation and axonal injury through the activating of the microglial MyD88-and TRIF-dependent pathways) requires the bridging adaptor, cells (Marusic et al., 2008). Blocking of the 5-LOX also delay the ap- TRAM, in order to transmit the signals downstream of TRIF (Cui et al., pearance of the EAE signs (Marusic et al., 2008). Thus, 5-LOX sup- 2014). The TLR3- and TLR4-mediated recruitment of the TRIF cause the pression may have therapeutic potential for treatment of the CNS-re- coalition of the TRAF6 and TRAF3 and then after TRAF3 leads to the lated demyelinating disorders such as MS. It has been demonstrated TBK-1-mediated activation of IRF3 and the expression of type I IFNs, that a double suppressor of the COX-2/5-LOX has protective effects while TRAF6 elicits the RIP kinase-1 and subsequent NF-κB activation against EAE through the reducing of the expression of MHC class II- and (Cui et al., 2014, De Nardo, 2015). costimulatory molecules, decreasing the proinflammatory cytokine The infiltrated immune cells and CNS resident cells express several production, promoting of the IL-10 production by macrophages and types of the TLRs and their expression are elevated in MS and EAE microglia, and preventing of the Th1- and Th17 cell differentiation disease (Podda et al., 2013). The contribution of the TLRs, in particular (Kong et al., 2016). TLR2, TLR3, TLR4, TLR7 and TLR9 in the MS and EAE development has The beneficial effects of the ginger in patients with rheumatoid been studied (Podda et al., 2013). Different kinds of DAMP are derived arthritis and osteoarthritis have been related to the suppression of PGs from various neuronal compartments following the damage to the and LTs production (Srivastava and Mustafa, 1992). The dual sup- neurons (Thundyil and Lim, 2015). The elevated expression of a pression of the cyclooxygenase and 5-LOX may be therapeutically more member of DAMP such as HMGB1, HSP70, versican, serum amyloid A, effective with lesser side effects than non-steroidal anti-inflammatory gangliosides and biglycan was demonstrated in the MS patients and drugs (Grzanna et al., 2005). Ginger inhibits the PG synthesis through EAE mice (Chang et al., 2012, Malhotra et al., 2015, Mansilla et al., suppressing the COX-1 and COX-2 enzymes. Ginger also inhibits LT 2014, Mansilla et al., 2012, Mohan et al., 2010, Pender et al., 2003, production by suppressing the 5-LOX enzyme (Grzanna et al., 2005). Sternberg et al., 2016, Yokote et al., 2013). There are many evidences Therefore, MS patients may benefit from dual suppression of the PGs indicating that the TLR activation induce the CNS inflammation via the and LTs biosynthesis by ginger or its components. production of cytokines, NO and chemokines (Carty and Bowie, 2011). The anti-inflammatory impacts of the ginger and its ingredients may 5.11. Ginger down-regulates the toll-like receptors-related signaling exert partly through the influencing on the TLRs-related signaling pathways pathways (Figure 2). The repressive effects of ginger and some of its ingredients such as 6-gingerol and 1-dehydro-10-gingerdione on the Toll-like receptors (TLRs) are belong to the membrane-related pa- NF-κB were demonstrated (Lee et al., 2009). 6-Shogaol inhibits the thogen recognition receptors (PRRs) that perform principle roles in the activation of NF-κB induced by LPS (a TLR4 ligand) in a monocytic cell identification of the exogenous pathogen-associated molecular patterns line and then suppresses the LPS-induced iNOS and COX-2 expression (PAMP) and endogenous molecules that named as damage-associated (Pan et al., 2008, Park et al., 2009). 6-shogaol suppresses NF-κB, in- molecular patterns (DAMP) (Nemati et al., 2017). PAMP are originated terfere with the PI3K/Akt, IKK and MAPK activation, inhibits the from pathogenic microorganisms such as peptidoglycan, LPS, flagellin, MyD88- and TRIF-dependent signaling pathways, and inhibits the IKK and nucleic acids, while the most DAMP are derived from dying or which acts as an important kinase in the NF-κB activation (Pan et al., stressed host cells, for instance heat shock proteins (Cui et al., 2014). 2008, Park et al., 2009). Suppression of the TRIF pathway by 6-shogaol Activation of the TLRs by PAMP or DAMP result in the production of the results in the down-regulation of the NF-κB and IRF3 activation and cytokines and chemokines that potentiate the inflammatory reactions inhibition of the expression of their target genes, including COX-2 and (Cui et al., 2014). IFNs (Park et al., 2009). TBK1 has been introduced as a main target of Each TLR molecule is made up of three regions, including an ex- 6-shogaol in the TRIF-dependent pathways (Park et al., 2009). 6-sho- tracellular N-terminal domain that possess leucine rich repeats (LRRs) gaol also inhibits the ERK1/2 activation and suppresses the expression which recognize the ligand, a transmembrane part, and an intracellular of the MyD88, NOS2 and MMP-2 and MMP-9 (Villalvilla et al., 2014). C-terminal Toll/interleukin-1 (IL-1) receptor (TIR) domain (De Nardo, Further, 6-shogaol protects the microglia against LPS-mediated toxicity 2015). For most of TLRs, their engagement lead to their dimerization by suppressing the production of TNF-α and IL-1β, NO and PGE2, that causes the conformational alterations within the TIR domains, and through the downregulation of the MAPK, NF-κB, NOS and COX-2 (Ha then after recruit TIR domain-containing adaptor proteins, to start next et al., 2012). 6-shogaol prevents the LPS-induced dimerization of TLR4 signaling pathways (De Nardo, 2015). With the exception of TLR3, all and therefore suppresses the NF-κB activation and the COX-2 expression TLRs need MyD88 to start signal transduction (Nemati et al., 2017). (Ahn et al., 2009). In an animal model of oral carcinoma, it was also Upon TLR ligation, MyD88 is directly connected to the intracellular TIR observed that 6-shogaol exerts anti-carcinogenic effects through the domain and then recruit IRAK4 (De Nardo, 2015). The MyD88-IRAK4 down regulation of the NF-κB and AP-1 activity and subsequent in- interaction enhances the IRAK4 autophosphorylation and subsequent flammatory events such as expression of IL-1, IL-6, COX-2, TNF-α, iNOS recruitment of the IRAK1 and IRAK2 (Cui et al., 2014). Activation of the (Annamalai and Suresh, 2018). IRAKs causes the temporary recruitment of the TRAF6 to the complex, Zingerone also suppresses the LPS-induced TNF-α, IL-6 and IL-1β followed by its subsequent activation and release into the cytoplasm, production through the inhibiting of the TLR4-related signaling ele- where it creates a complex with TAK1, TAB1 and TAB2/3 (De Nardo, ments (such as MyD88, TRIF and NF-κB) in a mouse model of kidney 2015). This signaling process activates an IKK complex consisting of injury (Song et al., 2016). Moreover, zingerone exhibits hepato-pro- NEMO, IKKα and IKKβ, leading to the phosphorylation and degradation tective eff ects against LPS-induced liver damage through the suppres- of IκB (inhibitor of NF-κB) (Cui et al., 2014). After that, NF-κβ is acti- sing of the TLR4 expression, enhancing the levels of the IκBα (an en- vated and translocated into the nucleus, where initiates the gene ex- dogenous NF-κB inhibitor), inhibiting the MAPK signaling, reducing the pression of the inflammatory promoting elements such as cytokines and MyD88 and TRIF protein expression, preventing the IRF-3 activation, chemokines, iNOS and COX-2 (Cui et al., 2014). Further, TRAF6-related and reducing the TNF-α and IL-6 production (Lee et al., 2018) signaling also activates the IRF5, which reinforces the production of the (Table 3). pro-inflammatory cytokines (Cui et al., 2014). In parallel, TAK1 induces High mobility group box 1 (HMGB1), an endogenous TLR2 ligand, is the MAPK pathway and subsequent AP-1 and CREB activation, which secreted by immune cells and/or is released by damaged cells also lead to the reinforcement of the cytokine gene expression (De (Andersson et al., 2018). The count of macrophages and microglia ex- Nardo, 2015). In plasmacytoid dendritic cells (pDCs), the MyD88- pressing the HMGB1is increased in acute and RRMS (Andersson et al.,

67 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

2008). Moreover, the elevated expression of the HMGB1 was demon- target genes (such as TNF-α and IL-1β), as well as IRF3-target genes strated in the serum and in the PBMCs from RRMS and SPMS patients (such as IFN-β gene and IP-10) in the LPS-activated macrophages (Park (Malhotra et al., 2015, Sternberg et al., 2016). The results from ex- et al., 2012). MD-2 is introduced as a target molecule in the anti-in- perimental studies indicate that zingerone reduces the releasing of the flammatory effects of 1-dehydro-10-gingerdione (Park et al., 2012) HMGB1 from damaged and stimulated cells and decreases the expres- (Table 3). 6-Dehydrogingerdione also inhibits the LPS-stimulated sion of the HMGB1 receptors such as TLR2, TLR4 and RAGE (Lee et al., phosphorylation of the IκBα and prevents the translocation of NF-κBto 2017). Moreover, zingerone reduces the HMGB1-mediated expression the nucleus (Huang et al., 2014). of the adhesion molecules (such as ICAM-1, VCAM-1, and E-selectin), Galangin, a flavonoid separated from the ginger family has been diminishes the neutrophil migration, decreases the HMGB1-induced also demonstrated to have anti-inflammatory, antioxidant and anti- activation of the NF-κB and ERK1/2, and reduces the TNF-α and IL-6 apoptotic properties (Tomar et al., 2017). Galangin preserve the renal production (Lee et al., 2017)(Table 3). function and reduce the expression of the NF-κB along with proteins of In addition, the anti-inflammatory properties of the 1-dehydro-10- the MAPK pathway, such as p38, JNK and ERK1/2 in an animal model gingerdione take place mainly through the suppressing of the NF-κB and of nephrotoxicity (Tomar et al., 2017). preventing the NF-κB-induced gene expression such as iNOS, COX-2, Taken together, ginger or its component may reduce the releasing of and IL-6 (Lee et al., 2012). The phosphorylation of IκBα by IKKβ in DAMPs from damaged cells in the CNS, interfere with TLR ligation, macrophages is also suppressed by 1-dehydro-10-gingerdione (Lee suppress the TLR-related signaling pathways and eventually inhibit the et al., 2012). TLR4 plays a central role in the bacterial LPS recognition, gene expression of the pro-inflammatory parameters that may lead to however its activity depends to a co-receptor that named MD-2, which the attenuation of the autoimmune disorders like MS. TLR-related ele- is associated with the extracellular region of the TLR4 (Cochet and Peri, ments may consider as important molecular targets of ginger in the 2017). 1-dehydro-10-gingerdione inhibits the binding of the LPS to the prevention of inflammatory diseases. The identifying other ginger-de- MD-2 and diminishes the TLR4-mediated expression of the NF-κB/AP1- rived components that may interfere with aforementioned TLR-linked

Fig. 2. Some CNS-derived components (including HMGB1, HSP70, versican, gangliosides, biglycan, hyaluronan and serum amyloid A) are recognized by TLR2/TLR2 homodimer and TLR2/TLR1, TLR2/TLR6 and TLR2/TLR10 heterodimers which are expressed by a number of infiltrated leukocytes and residential cells within the CNS. Moreover, a number of pathogen-derived molecules (such as lipopolysaccharides) are recognized by TLRs. The activation of the TLR-related signaling pathways result in the induction of inflammatory responses during MS. Ginger and its components (GAC) has powerful inhibitory effects on the TLR-related signaling pathways.

68 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75 process need to be investigated in more studies. (Ortiz et al., 2013). Oxidative stress involve in the development of the MS-related brain 5.12. Ginger down-regulates the inflammasome-related responses lesions through the several mechanisms (Ortiz et al., 2013). Free radi- cals, ROS and RNS damage to the multiple fundamental biological Other amplifiers of the inflammatory responses are named in- molecules, including lipids, proteins, DNA and polysaccharides through flammasomes. Inflammasome activation causes the conversion of the the peroxidation and nitration processes (Adamczyk and Adamczyk- pro-IL-1β and pro-IL-18 to their mature forms, and pyroptosis, a kind of Sowa, 2016, Ortiz et al., 2013). The oxidative injury disturb the normal the inflammatory cell death, which allows the releasing of cytokines cellular functions and interrupt the neuronal homeostatic state, finally (Place and Kanneganti, 2018). Each inflammasome is composed of a lead to the cell death through the apoptosis (Nita and Grzybowski, sensor protein (such as NLRP3) that recognize a stimulator, an adaptor 2016). Indeed, the oxidized DNA is seen within the neuronal and glial molecule (is named ASC) and pro-caspase-1, as an effector protein nuclei, degenerating neurons and glial cells from MS patients (Mahad (Awad et al., 2018). In addition to DCs, macrophages and lymphocytes, et al., 2015). The axons and myelin cover also display the oxidized li- the inflammasomes are also expressed in neuronal, glial and endothelial pids in their structure (Mahad et al., 2015). Oxidative stress also da- cells (Awad et al., 2018, Place and Kanneganti, 2018). The inflamma- mages to the mitochondria, which interrupt the transporting of the somes are activated by a vast board of molecular patterns that named adenosine triphosphate along the axon, and eventually leads to the pathogen-(bacteria, viruses, fungi) or danger- (extracellular ATP, cho- neurodegeneration (Ohl et al., 2016). Furthermore, ROS also enhance lesterol crystals, fibrillar β-amyloid) associated molecular patterns or the myelin breakdown, oligodendroglial injury, and neuronal and ax- homeostasis-altering molecular processes (PAMP, DAMP and HAMP, onal damage (Ortiz et al., 2013). Additionally, elevated levels of NO- respectively) (Awad et al., 2018). The expression of the processed cy- related metabolites within the CSF are associated with the MS relapses, tokines by inflammasomes (including IL-1β and IL-18) are increased in suggesting that the NO also plays a role in the promotion of the CNS EAE mice and in patients with MS (Barclay and Shinohara, 2017). It has damages (Ortiz et al., 2013). In addition to the direct neurodegenera- been indicated that NLRP3 inflammasome-deficient mice were pro- tive effects, the oxidative stress participates in the reinforcement of the tected against the EAE development (Gris et al., 2010). Both ASC and inflammatory reactions through the activating of the NF-κB(Ortiz et al., caspase-1 molecules were also found to be important for EAE devel- 2013). The NO also trigger the COX-2 expression which in turn en- opment (Barclay and Shinohara, 2017, Gris et al., 2010). NLRP3 in- hances the PGE2 synthesis (Ortiz et al., 2013). flammasome perform a major role in the EAE development through the The cellular protective reactions against oxidative stress are largely induction of the Th1 and Th17 cell responses (Gris et al., 2010). The controlled by the nuclear factor erythroid 2–related factor 2 (Nrf2). NLRP3 inflammasome also increases the migration of leukocytes to the Nrf2 perform an important role in the establishing of the cellular CNS (Inoue et al., 2012a). Additionally, IFN-β, a frontline therapeutic homeostasis through the inducing the expression of a number of anti- agent for MS, suppresses the NLRP3 inflammasome activation (Barclay oxidant proteins and detoxification enzymes such as enzymes mediating and Shinohara, 2017, Inoue et al., 2012b). Some ginger-derived phy- glutathione (GSH) synthesis, thioredoxin (Trx) enzyme, heme oxyge- tochemicals are able to suppress the IL-1β and NLRP3 expression. It has nases and NADPH-quinone oxidoreductase (Ohl et al., 2016). been indicated that the pretreatment of the THP-1 macrophages with Ginger has antioxidant activities, which are attributed to the sho- shogaols prevents the reduction in the pro-caspase-1 and the en- gaols, gingerols, and other ketone-phenolic derivatives that have ben- hancement in the active caspase-1 mediated by LPS- and ATP stimu- eficial effects in attenuating the ROS-induced CNS injury (Hussein et al., lation (Ho and Chang, 2018). Moreover, gingerols and shogaols reduce 2017). Ginger supplementation attenuates the monosodium glutamate- the LPS-induced IL-1β and NLRP3 expressions in THP-1 macrophages mediated neurotoxicity through the several mechanisms, including re- (Ho and Chang, 2018)(Table 3). storation of the antioxidant enzymes such as superoxide dismutase The powerful inflammatory potential of inflammasomes makes (SOD) and CAT, improvement of the glutathione levels, prevention of them as attractive therapeutic targets for treatment of inflammatory the lipid peroxidation, inhibition of the NO production and scavenging disorders. The influences of the ginger and its active components on the of hydroxyl radical (Hussein et al., 2017)(Table 3). expression of the inflammasome-related ligands, binding of a ligand to Hyperglycemia induced-oxidative stress performs a critical role in inflammasome, activation of the inflammasome- mediated effector neuronal injury in diabetic brains (Simmons, 2012). Generation of the mechanisms, expression ASC and caspase 1 need to be clarified in future very large levels of the free radicals from the auto-oxidation of the studies. elevated amounts of the intracellular glucose contribute in the neuronal injury (Simmons, 2012). The elevated intracellular glucose stimulates 5.13. Ginger down-regulates the oxidative stress the oxidative stress that causes the excessive ROS and NO production (El-Akabawy and El-Kholy, 2014, Simmons, 2012). The frequency of The oxidative stress plays a main role in the development and ad- caspase-3 positive cells, the frequency of apoptotic cells and the iNOS vancement of MS (Ohl et al., 2016). The ROS and reactive nitrogen and TNF-α expression were increased in the diabetic brains (El- species (RNS) are among the powerful chemical agents inducing the Akabawy and El-Kholy, 2014). In an animal model of the diabetic- oxidative stress (Ohl et al., 2016). Within the CNS of EAE mice, the mediated damage in the brain, the treatment with ginger significantly microglia and recruited macrophages express elevated levels of ROS down-regulate the iNOS expression, decrease the frequency of apoptotic and produce large amounts of the oxidizing radicals such as superoxide, cells, reduce the frequency of caspase-3 positive cells and reduce the hydroxyl radicals, hydrogen peroxide and NO (Ohl et al., 2016). TNF-α expression (El-Akabawy and El-Kholy, 2014)(Table 3). Treatment of the EAE rats with the catalase (CAT), which eliminates the 6-shogaol inhibits the ROS production and MAPK-related signaling, H2O2, markedly reduce the severity of the disease (Ohl et al., 2016). but increases the expression of the some anti-oxidant elements such as Microglia express molecules that contribute in the ROS production such glutathione, hemeoxygenase-1 and quinone-1 via the induction of Nrf2 as NADPH oxidase and myeloperoxidase (Mahad et al., 2015). Further, (Park et al., 2016)(Table 3). The activation of the Nrf2 pathway may the chemokine CCL11 secreted from activated astrocytes also potentiate perform a protective function against MS by the induction of several the oxidative stress through the activating of the microglial NADPH antioxidant enzymes that act as the ROS scavengers and prevent the oxidase (Adamczyk and Adamczyk-Sowa, 2016). High amounts of the oxidative damage to the neurons and oligodendrocytes, and by the ROS cause injury to the brain endothelium and lead to the loss of the enhancing of the expression of antioxidant enzymes that decrease the BBB integrity, and subsequent leukocyte recruitment into the CNS microglial activation and restrict the myelin breakdown (Ohl et al., parenchyma (Ohl et al., 2016, Ortiz et al., 2013). In addition, iNOS 2016). expression is also enhanced in the lesions and in the CSF of MS patients 6-Shogaol also exhibit the potent neuroprotective actions against

69 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75 the H2O2- or LPS-mediated harmful effects on the glial cells (Choi et al., 5.14. Ginger down-regulates the expression of the chemokines and 2018). Furthermore, 6-shogaol decreases the levels of the iNOS, COX-2, chemokines receptors and phospho-NF-kB in the LPS-stimulated astrocytes (Shim et al., 2011). Additionally, 6-shogaol inhibits the expression of the apoptosis The leukocyte aggregation into the CNS is an essential step in the proteins Bax and caspase-3 in the H2O2-treated astrocytes (Kim and MS and EAE development that is controlled by chemokines (Jafarzadeh Kwon, 2013). The expression of the neurotrophic factors such as NGF et al., 2014a, Jafarzadeh et al., 2014b). Ginger decreases the leukocyte and GDNF are decreased in the H2O2-treated astrocytes, however, 6- infiltration into the CNS of EAE mice (Jafarzadeh et al., 2017b, shogaol prevent these negative effects (Kim and Kwon, 2013). Fol- Jafarzadeh et al., 2014d). CCL20 and its receptor CCR6 perform a lowing the oxidative stress, 6-shogaol protects astrocytes against oxi- principle role in the entering of the pathogenic Th17 cell in the CNS and dative damage via the promoting of the expression of neurotrophic CCR6-deficient mice are highly resistant against the EAE (Jafarzadeh factors (Kim and Kwon, 2013)(Table 3). et al., 2018a, Williams et al., 2014). Increased serum amounts of the Paradols also possess the anti-inflammatory and anti-oxidative ac- CCL20 were indicated in MS patients (Jafarzadeh et al., 2014a). Within tivities similar to shogaols (Chung et al., 2001). 6-paradol reduces the the CNS, the astrocytes produce CCL20 after activation with TNF-α, IL- NO production and IL-6 and TNF-α secretion in the LPS-stimulated 1β, IL-6, IL-9 and IL-17 (Ambrosini et al., 2003, Meares et al., 2012, microglia (Gaire et al., 2015). Administration of the 6-paradol to mice Zhou et al., 2011). The elevated expression of the CCL20 and CCR6 was with focal cerebral ischemia reduces the brain damage as estimated by indicated in the spinal cords of EAE mice and treatment with ginger infarction, neurological impairment and neuron survival (Gaire et al., decreases the CCL20 and CCR6 expression in the spinal cords 2015). 6-paradol administration also reduces the neuroinflammation in (Jafarzadeh et al., 2017b)(Table 3). focal cerebral ischemia by lessening the microglial activation and de- CCL22 acts as a chemokine for the CCR4-expressing cells, including creasing the frequency of cells expressing iNOS and TNF-α (Gaire et al., DCs, Th2-, Treg-, NK- and NKT cells (Jafarzadeh et al., 2015b, Safa 2015)(Table 3). et al., 2016). The administration of the neutralizing antibody against Experimentally, it was also indicated that zingerone reduces the CCL22 reduces the EAE clinical signs and decreases the lymphocyte and cisplatin-induced histopathological changes in the ovarian and uterine, macrophage infiltration in the CNS (Dogan et al., 2011). The CCR4- through increasing the activity of antioxidant enzymes (such as SOD, deficient mice also exhibit low grade of EAE symptoms (Forde et al., CAT and GPx) and GSH production (Kaygusuzoglu et al., 2018). 2011). Moreover, the number of CNS-infiltrated leukocytes was re- − − − − Moreover, zingerone reduces the levels of the inflammatory markers duced in the double knockout CCR6 / and CCR4 / mice in com- NF-κB, TNF-α, IL-1β, IL-6, COX-2 and iNOS in cisplatin-induced damage parison with wild type mice (Moriguchi et al., 2013). in ovarian and uterine (Kaygusuzoglu et al., 2018). Zingerone also It has been also shown that the CCL22 and CCR4 expression in the suppresses the oxidative stress and age-related inflammation via the spinal cords of EAE mice was increased as compared with healthy mice inhibition of the MAPK/NF-κB pathway (Kim et al., 2010)(Table 3). (Jafarzadeh et al., 2017b, Jafarzadeh et al., 2018a). The expression of In a rat animal model, the treatment with a 6-gingerol-rich fraction CCL22 and CCR4 in EAE mice treated with ginger was diminished in prevents the chlorpyrifos-induced expression of the H202, mal- comparison with the non-treated control EAE group (Jafarzadeh et al., ondialdehyde (MDA), myeloperoxidase (MPO), NO, TNF-α and caspase- 2017b)(Table 3). Similar to CCL20, within the CNS, the CCL22 is 3 in the brain, ovary and uterus (Abolaji et al., 2017). Further, 6-gin- produced by microglia and astrocytes (Columba-Cabezas et al., 2002, gerol-rich fraction restores the activities of the antioxidant enzymes Ding et al., 2015). The NF-κB induction in the microglia and astrocytes such as CAT, SOD, glutathione peroxidase (GPx), and glutathione S- lead to the expression of the some inflammatory promoting mediators transferase as well as glutathione production in the chlorpyrifos-ex- (Leibowitz and Yan, 2016). As mentioned, the ginger and some of its posed rats (Abolaji et al., 2017). The 6-gingerol also exerts preventive efficient components reduce the NF-κB activation (Luettig et al., 2016). effects against the ischemia/reperfusion-induced intestinal mucosa da- Therefore, the inhibitory effects of ginger on the expression of CCL20 mage by suppressing the ROS formation and p38 MAPK activation (Li and CCL22 may perform in part through the suppression of NF-κB. et al., 2017). Moreover, three kinds of gingerols including 6-, 8- and 10- The increased levels of RANTES and MCP-1 were also indicated in gingerol reduce the MDA quantities and MPO activity in the colon MS patients (Lomakin et al., 2016, Mori et al., 2016). Ginger reduces tissue in an animal model of ulcerative colitis (Zhang et al., 2017) the monocyte and macrophage migration through the suppression of (Table 3). the RANTES production (Ezzat et al., 2018). The inhibition of RANTES It should be also noted that the oxidative agents such as hydroxyl production by ginger not only attenuates the inflammation, but also radical and superoxide also play a main role in the development of decreases the T cell activation and IFN-γ production (Ezzat et al., 2018). other neurologic diseases, such as Parkinson's disease which is char- The reducing impacts of ginger on the MCP-1 production have been also acterized by the incrementally degeneration of the dopaminergic neu- indicated (Grzanna et al., 2004, Villalvilla et al., 2014). rons (Choi et al., 2018). It has been reported that zingerone control CXCL10 acts as a chemokine for CXCR3-expressing cells, in parti- oxidative stress via enhancing the expression of anti-oxidant enzymes cular Th1 cells (Safa et al., 2016, Vazirinejad et al., 2014). CXCR3 is such as CAT and GPx and improving of the SOD activity in the animal expressed on the > 90% of the T lymphocytes in the CSF of MS patients models of Parkinson's disease (Choi et al., 2018). (Safa et al., 2016, Vazirinejad et al., 2014). Elevated CXCL10 levels Ginger extract also inhibits the oxidative stress through the de- were also found in the CSF samples from MS patients (Khaibullin et al., creasing in the lipid peroxidation and increasing in the protein levels 2017). The CXCL10/CXCR3 also play a fundamental role in the MS and activity of SOD, CAT, GPx, GST, GSH, glutathione reductase (GR), pathogenesis (Vazirinejad et al., 2014). It was indicated that the ginger quinine reductase (QR) in the brain of pesticides-exposed rats (Sharma suppresses the CXCL10 expression in a macrophage cell line, with si- and Singh, 2012). Thus, ginger is a reliable source of the putative sti- milar characteristics to microglial cells, and in human synoviocytes mulators for the ROS scavenging enzymes SOD, CAT, and GPx that may (Grzanna et al., 2004, Phan et al., 2005). The suppressive impacts of 6- consider as new therapeutic agents for the treatment of the neurologic shogaol on the CCL17 production were also indicated in an animal diseases such as MS. The aforementioned explanations clearly indicate model of allergic dermatitis (Park et al., 2016). that ginger and its ingredients have potential to reduce oxidative agents In addition to the effects of chemokines, the binding of the cell and enhance the antioxidative elements. Therefore, MS patients may adhesion molecules located on the surface of endothelial cells (such as benefit from powerful antioxidant activity of ginger. ICAM-1 and VCAM-1) to their cognate ligands (such as integrins) on the immune cells perform an essential role in the movement of leukocytes into the CNS (Legroux and Arbour, 2015). Gingerenone reduces the TNF-α and LPS-induced VCAM-1 expression (Kim et al., 2018).

70 A. Jafarzadeh, M. Nemati Journal of Neuroimmunology 324 (2018) 54–75

Zerumbone also reduces the expression of ICAM-1 in a mouse model of (Table 3). diabetic kidneys (Tzeng et al., 2013). In addition to doses, the administration routes and the duration of Collectively, ginger and its constituents may have the potential to treatment vary in different studies. Overall, according to current studies modulate the chemokines, chemokine receptors and adhesion mole- on the promising therapeutic potential of ginger and its active con- cules, and reduce the migration of pathogenic cells into the CNS. The stituents, more clinical studies are necessary to investigate the effects of involvement of a large number of chemokines (such as CCL2, CCL3, multiple doses and the different dosing program, and to determine the CCL5, CCL7, CCL8, CCL11, CCL17, CCL19, CCL21, CXCL1, CXCL9, most effective doses and their safety. CXCL10, CXCL11, CXCL12 and CXCL13) and their receptors was re- In conclusion, a complex network of immunopathological-, in- ported (Cheng and Chen, 2014). The impacts of ginger and its active flammatory- and oxidative parameters take part in the MS pathogen- components on the principle elements that mediating the movement of esis. The currently used drugs for MS treatment are not fully efficient the pathogenic cells into the CNS (including chemokines, chemokine and induce considerable adverse effects (Baecher-Allan et al., 2018, receptors and adhesion molecules) remains to be more clear in future Namjooyan et al., 2014). Of note, ginger has the capability to interfere studies. with all of the major elements participating in the MS development due to its immunomodulatory, antioxidant, and anti-inflammatory proper- 6. Safety of ginger ties. In traditional medicine, ginger was used for treating a vast board of illnesses such as arthritis, stomachache, diarrhea, nausea, respiratory Ginger was usually considered as a safe medicinal plant at dosages diseases, toothache and gingivitis (Grzanna et al., 2005). Ginger also of up to 4 grams/day and included in the FDA-approved list of “gen- has the potentials to attenuate the symptoms in a number of neurolo- erally regarded as safe”(Ryan and Ginger, 2010). The results of a sys- gical diseases such as epilepsy, migraine, Alzheimer's disease and Par- tematic review study in patients with type 2 diabetes mellitus indicate kinson's disease (Choi et al., 2018). In addition, the treatment of EAE that the prolonged daily consumption of ginger powder (at dosages up mice with ginger ameliorates the disease-related symptoms and im- to 3 grams/day for 6-12 weeks) has no serious adverse effects and prove the immunological and inflammatory alterations (Jafarzadeh complications (Zhu et al., 2018). However, it has been reported that et al., 2017a, Jafarzadeh et al., 2017b, Jafarzadeh et al., 2015a, ginger causes few minor adverse events such as heartburn, abdominal Jafarzadeh et al., 2014d). This is worthy to identify the novel bio- discomfort and mild diarrhea, at doses of 6 grams and higher (Ryan and markers involving in the MS acceleration and progression, and to Ginger, 2010). The various adverse effects were also attributed to evaluate the modulatory effects of ginger and its compounds on these ginger consumption in pregnant women for reducing nausea and vo- parameters in future studies. No considerable adverse effects (except miting such as headache, abdominal discomfort, diarrhea, heartburn, the platelet aggregation and probably spontaneous abortions) have arrhythmia, intolerance, allergic reaction, dizziness and drowsiness been indicated in the preclinical studies on the ginger (Choi et al., 2018, (Stanisiere et al., 2018). There are also controversies regarding the Stanisiere et al., 2018), however, more investigations are required to association of ginger consumption and spontaneous abortions in preg- examine the side effects of the high-doses or long-period administration nant women (Stanisiere et al., 2018). It has been also reported that of ginger or its ingredients. The standardization of the ginger and its ginger may reduce platelet aggregation or interact with the antic- constituents in the preclinical therapeutic program will provide valu- oagulant drug warfarin (Ryan and Ginger, 2010). However, it has been able insight regarding the possible using of ginger as an effective indicated that the ginger administration at dosages up to 4 grams/day therapeutic agent. In this review, we provide a better understanding has not changed platelet aggregation (Ryan and Ginger, 2010). More- concerning the pharmacological potentials of ginger and its con- over, the interaction of ginger with warfarin was not approved in an- stituents for possible utilizing in the managing of MS. Based on the other study (Ali et al., 2008). Although, ginger acts as an im- numerous beneficial effects and insignificant side effects, ginger may be munomodulating agents, there are no reports regarding the association a promising candidate for the treatment of MS. This review encourages of the ginger and susceptibility to infection. Interestingly, some anti- more investigations to evaluate the possible therapeutic potential of infective properties were attributed to ginger (Adamczyk and ginger or its derivatives for managing of MS. Adamczyk-Sowa, 2016, Dyab et al., 2016, Gaus et al., 2009). Conflict of interest 7. Effective doses of ginger and its active components The authors have no any conflict of interest. In the studies summarized in the Table 2, the in vivo effective im- munomodulatory doses ranged from 28 to 720 mg/kg/day for ginger Acknowledgments extract, and were 10 and 50 mg/kg/day for 6-shogaol. In the studies summarized in the Table 3, the in vivo effective anti-inflammatory and Research reported in this publication was supported by a grant [NO: anti-oxidative doses ranged from 200 to 500 mg/kg/day for ginger 958110] from the National Institutes for Medical Research extract, were 5- and 10 mg/kg/day for 6-shogaol, were 25-, 30- and 50 Development (NIMAD), Tehran, Iran. mg/kg/day for 6-gingerol, were 30 mg/kg/day for 8- and 10-gingerol, were 50- and 100 mg/kg/day for a 6-gingerol-rich fraction, ranged References from 0.18- to 50 mg/kg/day for zingerone, and were 1-, 5-, and 10 mg/ kg (and 2.5 μmol) for 6-paradol. In human studies the ginger powder Abolaji, A.O., Ojo, M., Afolabi, T.T., Arowoogun, M.D., Nwawolor, D., Farombi, E.O., was used in 500-, 1000-, and 1500 mg/day for 3 months, 2 months and 2017. Protective properties of 6-gingerol-rich fraction from Zingiber officinale (Ginger) on chlorpyrifos-induced oxidative damage and inflammation in the brain, 6 weeks, respectively. ovary and uterus of rats. Chem. Biol. Interact. 270, 15–23. The in vitro effective immunomodulatory doses ranged from 1 μg/ml Adamczyk, B., Adamczyk-Sowa, M., 2016. New insights into the role of oxidative stress to 10 mg/ml for ginger extract, ranged from 6.5 to 100 μM for 6-gin- mechanisms in the pathophysiology and treatment of multiple sclerosis. Oxidative μ Med. Cell. Longev. 2016, 1973834. gerol, and ranged from 25 to 100 M for 8- and 10- gingerol (Table 2). Ahn, S.I., Lee, J.K., Youn, H.S., 2009. Inhibition of homodimerization of toll-like receptor The in vitro effective anti-inflammatory and anti-oxidative doses were 4 by 6-shogaol. Mol. Cell 27, 211–215. 25, 50, or 100 μg/ml for ginger extract, ranged from 1- to 30 μM (and Ahui, M.L., Champy, P., Ramadan, A., Pham Van, L., Araujo, L., Brou Andre, K., et al., from 0.25- to 1 μg/ml) for 6-shogaol, were 10 and 20 μM for 8-shogaol, 2008. Ginger prevents Th2-mediated immune responses in a mouse model of airway inflammation. Int. Immunopharmacol. 8, 1626–1632. were 40-, 50- and 80 μM or 0.25-, 0.50- and 1 μg/ml for 6-gingerol, Ali, B.H., Blunden, G., Tanira, M.O., Nemmar, A., 2008. Some phytochemical, pharma- were 10-, 25- and 50 μM for zingerone, were 1, 5, 10, or 20 μg/ml for 6- cological and toxicological properties of ginger (Zingiber officinale Roscoe): a review – paradol, and were 3-, 10- and 30 μM for 1-Dehydro-[10]-gingerdione of recent research. Food Chem. Toxicol. 46, 409 420.

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