Table 1.
Other antioxidant compounds tested in experimental models of MS.
| Drug Class | Author, Year [Ref] | Animal Model | Main Findings |
|---|---|---|---|
| Combined matrix metalloproteinase (MMP) and TNF-alpha inhibitor | Clements et al., 1997 [203] | Male Lewis rats aged 5–8 weeks with EAE | Reduction of clinical signs and weight loss, a decrease in MMP activity in the CSF, a marked increase of the MMP matrilysin, and a modest increase in the MMP 92 kDa in the spinal cord. |
| Matrix metalloproteinase (MMP) inhibitor | Liedtke et al., 1998 [204] | SJL/J mice with EAE | Clinical improvement (blocking and reversal of acute disease, reduced number of relapses, improvement in clinical scores). Significant decrease in demyelination and glial scarring and in central nervous system gene expression for TNF alpha and fasL and an increase in IL-4 expression. |
| EUK-8 (synthetic catalytic scavenger of oxygen-reactive metabolites) | Malfroy et al., 1997 [205] | PL/J (H-2u) mice aged 3–8 months with EAE | Complete recovery after 40 days of EAE mice pretreated with EUK-8 and significant improvement after treatment with EUK-8 4 days after EAE induction. |
| Drugs acting on heme oxygenase 1 (HO-1) | Liu et al., 2001 [206] | Adult male Lewis rats with EAE | Hemin (HO-1 inducer) improved the clinical course of EAE and reduced inflammatory changes in the spinal cord, while tin mesoporphyrin (HO-1 inhibitor) worsened the clinical course of EAE and increased non-significantly inflammatory changes in the spinal cord. |
| t-butyl hydroxy anisole (phase 2 enzyme inducer) | Mohamed et al., 2002 [207] | Lewis rats aged 10–12 weeks with EAE | Clinical improvement of EAE, reduction in perivascular lymphocyte infiltration, and increase in red cell GSH concentrations. |
| Thymoquinone | Mohamed et al., 2002 [208] | Female Lewis rats with EAE | Prevention (if administered previously to EAE induction) or reversal (if administered after EAE induction) of clinical symptoms, perivascular inflammation, and decrease in spinal cord GSH levels. |
| Silibinin (Silybum marianum fruit extract) | Min et al., 2007 [209] | Female, 6-week-old C57BL/6 mice | Prevention or attenuation of clinical signs. Reduction of histological signs of demyelination and inflammation in the spinal cord. Down-regulation of the inflammatory cytokines IL-12 and IL-2 and slight upregulation of the anti-inflammatory cytokine IL-4 in a concentration-dependent manner in splenocytes. |
| ABS-75 (fullerene derivative) | Basso et al., 2008 [210] | Non-obese diabetic (NOD) mice with EAE | Clinical improvement associated with reduced axonal loss and demyelination, and halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord. |
| GEMSP (mixture of fatty acids, vitamins, and amino acids or their derivatives; and Poly-L-Lysine) | Mangas et al., 2008 [211] | 10–11 weeks Lewis 1A female rats with EAE | Complete clinical reversal of EAE, reduction in brain leukocyte infiltration, and preserved immunoreactivity to conjugated methionine antibodies in the motoneurons of the ventral horn. |
| Genistein (derivative of soy) | De Paula et al., 2008 [212] | 8–12 weeks old female C57BL/6 mice with EAE | Significant improvement in clinical symptoms, modulating pro- and anti-inflammatory cytokines in the CNS and splenocytes (upregulation of IL-10 and downregulation of IFN-gamma, TNF-alpha, and IL-12), and decreasing rolling and adhering of leukocytes to the CNS. |
| Tempamine (TMN) encapsulated in the intraliposomal aqueous phase of pegylated nanoliposomes |
Kizelsztein et al., 2009 [213] | Female C57BL/6 mice with EAE | Significant improvement of clinical symptoms and reduction in the expression of mRNA for IFN-gamma and TNF-alpha in the brain. |
| Ethanol extract of saffron (Crocus sativus L.) | Ghazavi et al., 2009 [214] | 8-week-old male C57BL/6 mice with EAE | Significant clinical improvement, decrease of inflammatory changes in the brain, increase in serum TAC, and non-significant changes in serum NO levels. |
| Ethylene diamine tetra acetic acid (EDTA) | Mosayebi et al., 2010 [215] | 6–8-week-old male C57BL/6 mice with EAE | Significant delay in the time of onset and a significant reduction in severity of the EAE. Reduction in inflammatory changes and density of mononuclear infiltration in the CNS. Increase in total serum antioxidant power, decrease in serum NO levels and decrease in levels of IFN-gamma in cellular cultures of splenocytes. |
| Aloe vera | Mirshafiey et al., 2010 [216] | 6–8-week-old male C57BL/6 mice with EAE | Significant delay in the time of onset and a significant reduction in severity of the EAE. Reduction in inflammatory changes and density of mononuclear infiltration in the CNS. Increase in total serum antioxidant power, decrease in serum NO levels and decrease in levels of IFN-gamma in cellular cultures of splenocytes. |
| Erythropoietin | Chen et al.,, 2010 [217] | 6–8-week-old male C57BL/6 mice with EAE | Significant clinical improvement. Significant increase in expression of HO-1 mRNA in the spleen and the CNS. Significantly decrease in the expression of interferon-γ, interleukin (IL)-23, IL-6, and IL-17 mRNA, and increase in the expression of IL-4 and IL-10 mRNA in CNS. Significant decrease in the ratio of both T helper type 1 (Th1) and Th17 lymphocyte subsets isolated from CNS and an increase in the ratio of splenic regulatory CD4 T cells. |
| Hydralazine (acrolein scavenger) | Leung et al., 2011 [218] | 8-week-old male C57BL/6 mice with EAE | Significant delay and improvement of clinical symptoms. Significant decrease of demyelination in the spinal cord. |
| Spermidine | Guo et al., 2011 [219] | 6–8-week-old female C57BL/6 mice with EAE | Significant improvement of clinical symptoms, including optic neuritis. Significant improvement of demyelination in the spinal cord and optic nerve and prevention of cell loss and apoptosis in the retinal ganglion cell layer. |
| L-cycloserine (inhibitor of Ceramide synthase 6, CS6) | Schiffmann et al., 2012 [220] | 8–10 week-old female C57BL/6 or IFN-γ KO with EAE | Remission of the disease related to prevention of the increase in C(16:0)-Cer (reflecting a decrease in CS6 expression) and iNOS/TNF-α expression. |
| Aqueous extract of North American ginseng | Bowie et al., 2012 [221] | C57BL/6 6 week-olf female mice with EAE | Significant decrease in clinical signs of EAE, levels of circulating TNF-α, and CNS immunoreactive iNOS and demyelination scores. |
| Safinamide and flecainide (sodium channel-blocking agents) | Morsalli et al., 2013 [222] | Male and female Dark Agouti rats | Pretreatment and treatment with these drugs caused significant improvement of neurological deficits and protection against neurological deficit and axonal degeneration associated with reduction in the CNS of the activation of microglia/macrophages. |
| MitoQ (mitochondria-targeted antioxidant) | Mao et al., 2013 [223] | 10-week-old C57BL/6 mice with EAE | Pretreatment and treatment with this drug caused significant improvement of neurological deficits, reversed the increase of mRNA expression of CD4, CD8, CD11b, IL1, IL6, IL10, IL17, TNFα, NOS2, and NFkB in the spinal cord, and induced upregulation of the anti-apoptotic gene STAT3 in the spinal cord. |
| Sulforaphane | Li et al., 2013 [224] | 8–10 week-old female C57BL/6 mice with EAE | Inhibition of development and severity of EAE. Decrease of inflammation and demyelination in the spinal cord. Prevention or reversion of the increased MDA levels expression of MMP-9 and decreased expression of Nrf2, HO-1, and NQO1 in the brain caused by EAE. Reversion of increased IL-17A-secreting Th17 cells in splenocytes. |
| Astragaloside IV (a natural saponin molecule) | He et al., 2013 [225] | 6-week-old female C57BL/6 mice with EAE | Improvement of clinical signs of EAE. Inhibition or reversion of the increase of ROS and pro-inflammatory cytokine levels, downregulation of SOD and GSH-Px activities, increase of iNOS, p53, and phosphorylated tau, and decrease of ratio of Bcl-2/Bax in CNS caused by EAE |
| Β-asarone modified astragaloside IV (a natural saponin molecule) | Zhao et al., 2023 [226] | 6–8 week-old female C57BL/6 mice | Improvement of clinical signs of EAE. Suppression of inflammatory infiltration and astrocyte/microglial activation and reduction of demyelination in the brain. |
| R-flurbiprofen | Schmitz et al., 2014 [227] | 10–12 week old female C57BL6/J mice with primary progressive EAE and 10–12 week female SLJ mice with relapsing-remitting EAE in SJL mice | Prevention of attenuation of clinical signs in both models of EAE. Decrease of immune cell infiltration and microglia activation and inflammation in the spinal cord, brain, and optic nerve and attenuation of myelin destruction and EAE-evoked hyperalgesia. Increase of CD4(+)CD25(+)FoxP3(+) regulatory T cells, CTLA4(+) inhibitory T cells, and IL-10, Important decrease of upregulation of pro-inflammatory genes in the spinal cord. Association of these effects to the increase of plasma and cortical endocannabinoids and decreased spinal prostaglandins. |
| Apocynin (NADPH oxidase assembly inhibitor) | Choi et al., 2015 [228] | Female C57BL/6 mice | Significantly marked clinical improvement of EAE associated with suppression of demyelination, reduced infiltration by CD4, CD8, CD20, and F4/80-positive cells, reduced induction of pro-inflammatory cytokines in cultured microglia, and inhibition of free radicals production and blood–brain barrier disruption. |
| Flavocoxid (dual cyclooxygenase and 5-lipoxygenase inhibitor) | Kong et al. 2016 [229] | Female C57BL/6 mice 6–10 weeks old | Significant clinical improvement of EAE. Decrease in COX2, 5-LO, IL12, IL23, IL17, IFNγ and increase in IL10 in the spinal cord. Decrease of MHCII, CD40, CD80, CD86, COX2, 5-LO, IL12 and IL6, and increase of IL-10 in primary macrophages. Increase of Arg1, Ym1, CD206, TGFβ1, IL10 and decrease of iNOS and IL-12 in macrophages and microglia. Inhibition of Th1/Th17 differentiation. |
| Hydrogen-rich water | Zhao et al., 2016 [230] | C57BL/6 mice 6–8 weeks old | Significant clinical improvement of EAE (delay and reduction of clinical severity). Inhibition of inflammatory infiltration and demyelination of CNS. Prevention of infiltration by CD4+ population and inhibition of Th17 cell differentiation in CNS and peripheral immune organs. |
| Arctigenin (lignan present in the extract from Arctium lappa) | Li et al., 2016 [231] | Female C57BL/6 mice 6–8 weeks old | Significant clinical improvement of EAE. Decreased inflammation and demyelination, inhibition of Th1 and Th17 cells in peripheral immune organs. Suppression of the Th1 cytokine IFN-γ, the transcription factor T-bet, the Th17 cytokines IL-17A, IL-17F, and the transcription factor ROR-γt. Inhibition of Th17 cells (but not Th1 cells) in the CNS. Activation of s AMPK, inhibition of phosphorylated p38, and upregulation of PPAR-γ. |
| 3H-1,2-dithiole-3-thione (D3T, a potent inducer of antioxidant genes and glutathione biosynthesis) | Kuo et al., 2016 [232] | C57BL/6 mice and Nrf2 deficient mice (Nrf2−/−) with its corresponding controls (Nrf2+/−) of 7–10 weeks of age | Significant clinical improvement of EAE. Suppression of the activation of dendritic cells. Suppression of IL-23 and co-stimulatory molecules in dendritic cells through induction of Nrf2. Inhibition of Th1 and Th17 differentiation and activation of microglia. |
| Pramipexole (D2/D3 receptor agonist with antioxidant actions) | Lieberknecht et al., 2017 [233] | Female C57BL/6 mice with EAE | Prevention of development of clinical signs of EAE. Blocking of neuroinflammatory response, demyelination, and astroglial activation in spinal cord. Inhibition of the production of inflammatory cytokines (IL-17, IL-1β, and TNF-α) in peripheral lymphoid tissue. Reversion of effects of EAE in reactive oxygen species, glutathione peroxidase, parkin, and α-synuclein in the spinal cord and striatum. |
| Despramipexole | Buonvicino et al., 2020 [234] | Female non-obese diabetic NOD/ShiLtj and C57BL/6 mice with EAE | Delay in progression of clinical symptoms. Increase in survival, counteracted reduction of spinal cord mitochondrial DNA content, and reduced spinal cord axonal loss of mice. |
| TEMPOL (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, membrane-permeable radical scavenger) | Neil et al., 2017 [235] | Female C57BL/6J (Jackson Labs) or SJL/J of 8–10 weeks of age | Prevention of EAE by delayed onset, reduced incidence, and reduction of clinical severity of the disease. Decrease in microglial activation and fewer inflammatory infiltrates and axonal damage. Decrease in production of INF-γ and TNF-α by T-cells, decrease in levels of MHC class II expression and CD40 in myeloid and myeloid-dendritic cells. Increase in CD8+ T cell populations and CD4+FoxP3+ regulatory populations. |
| β-Caryophyllene (sesquiterpene derivative) | Fontes et al., 2017 [236] | Female C57BL/6 mice 8–12 weeks old | Significant improvement of clinical score and severity of EAE. Significant decrease in the number of inflammatory infiltrates and attenuation of neurological damage. Inhibition of H2O2, NO, TNF-α, IFN-γ, and IL-17 production. |
| BJ-2266 (6-thioureido-derivative) | You et al., 2017 [237] | C57BL/6 mice and OT-II mice | Significant suppression of EAE disease progression. Reduction of generation of Th1 and Th17 cells through inhibition of JAK/STAT phosphorylation. |
| D-aspartate | Afraei et al., 2017 [238] | Female C57BL/6 mice 8 weeks old | Significant attenuation in the severity and delay in the onset of the disease. Reduction of demyelination, inflammation, and degeneration in the CNS. Significant decrease in serum IL-6 levels. Non-significant increase in SOD and glutathione-reductase activities and TAC in serum. |
| 18β-glycyrrhetinic acid | Kamisli et al., 2018 [239] | Female C57BL/6 mice | Significant clinical improvement. Reversion of histological and immunological alterations caused by EAE. Increased brain levels of TBARS levels and decreased GPx, SOD, CAT, and GSH levels in brain tissue. Decreased caspase-3 and IL-17 activity in brain tissue. |
| Ethanol extract of Glycyrrhizae Radix | Yang et al., 2019 [240] | Female C57BL/6 mice aged 5 weeks | Clinical improvement of EAE signs associated with a decrease of antigen-specific TH1 and TC1 populations and an increase of CD8+IL-17A+ (TC17) population. Reduction in IFN-γ+ T cell populations, the expressions of cell adhesion molecules (CAMs), and secretions of cytokines containing IFN-γ and a chemokine IFN-γ-induced protein 10 (IP-10) in splenocytes in culture. Decrease in NO production and secretion of TNF-α and IP-10 in IFN-γ-stimulated BV2 cells in culture. |
| Oligomeric proanthocyanidin (OPC), the most effective component of grape seed extract | Wang et al., 2019 [241] | Male C57BL/6J mice with cuprizone-induced demyelination | Attenuation of abnormal behavior reduced demyelination and increased expression of myelin basic protein and expression of O4+ oligodendrocytes in the corpus callosum. Reduction in numbers of B and T cells, activation of microglia in the corpus callosum, and inhibition of secretion of inflammatory factors. |
| Gold nanoparticles and polyethylene glycol | Aghaie et al., 2019 [242] | Female C57BL/6 mice aged 8–10 weeks with EAE | Significant decrease in the severity of EAE symptoms. Significant decrease in the number and severity of cells’ infiltration and demyelinated lesions in the spinal cord. Significant increase in IL-27 and decrease in IL-23 levels (only for gold nanoparticles). |
| Oenothera biennis L. and Hypericum perforatum L. extracts | Selek et al., 2019 [243] | 8–10-week-old C57BL/6J mice | Significant decrease in the severity of EAE symptoms. Significant decrease in brain tissue MOG and MBP. Significant decrease in the TOS and OSI values and increase in TAS in brain tissue. Significant decrease in myelin loss and amyloid deposition on vascular walls, in the cytoplasm of the neurons, and in the intercellular space. |
| Mitochondria-Targeted Antioxidant SkQ1 | Fetisova et al., 2019 [244] | In vitro MS model of the primary oligodendrocyte culture of the cerebellum, challenged with lipopolysaccharide (LPS). | SkQ1 accumulated in the mitochondria of oligodendrocytes and microglial cells and prevented LPS-induced inhibition of myelin production in oligodendrocytes. |
| Ellagic acid (a polyphenol found in numerous fruits and vegetables with antioxidant actions) | Khodaei et al., 2019 [245,246] | 6–9 week-old male C57BL/6 mice with cuprizone-induced demyelination | Significant improvement of EAE symptoms. Decrease in MDA levels, increase in TAC, and GSH/GSSG ratio in muscle tissue. Increase in mitochondrial dehydrogenase. SOD and catalase activities, mitochondrial ATP levels and mitochondrial GSH/GSSG ratio, and decrease in mitochondrial depolarization in muscle tissue. Increase in mitochondrial complex I, II, and IV activities in Sirt3 level and Sirt3 expression in muscle tissue. |
| Tetrapeptide N-acetyl-ser-asp-lys-pro (Ac-SDKP) | Pegman et al., 2020 [247] | 10-week-old female C57BL/6 mice with EAE | Significant improvement of EAE symptoms. Decrease in inflammatory infiltration and demyelination in hippocampus oligodendrocytes. Reduction of reactive oxygen species, MDA levels, and NOS production. Increase in GSH levels, GPx and HO-1, and total antioxidant activities. Decrease in caspase-12 and CHOP expression in the hippocampus-resident oligodendrocytes. Decrease in the activation of the proinflammatory cytokines IL-6 and IL-1β and increase in levels of the anti-apoptotic proteinBcl2. |
| Acteoside (AC), an active compound from the medicinal herb Radix rehmanniae | Li et al., 2020 [248] | 10–14-week-olf female C57BL/6 N mice with EAE | Significant improvement and delay of EAE symptoms. Inhibition of inflammation/demyelination, and peripheral activation and CNS infiltration of encephalitogenic CD4+ T cells and CD11b+ activated microglia/macrophages in the spinal cord Decrease in peroxynitrite production down-regulation of the expression of iNOS and NADPH oxidases, and inhibition of neuronal apoptotic cell death and mitochondrial damage in the spinal cords. |
| GYY4137 (Hydrogen Sulfide Donor) | Lazarević et al., 2020 [249] | Dark Agouti rats or C57BL/6 mice with EAE | Increase in TGF-β expression and production in dendritic cells and significant reduction of IFN-γ and IL-17 production in the lymph node and spinal cord T cells obtained from mice immunized with CNS antigens. Decrease in the proportion of FoxP3+ regulatory CD4+ T cells in the lymph node cells and the percentage of IL-17+ CD4+ T cells in the spinal cord cells after culturing with GYY4137. |
| Shikonin (extract from plants of the Boraginaceae family) | Nasrollahzadeh Sabet et al. 2020 [250] | Female C57BL/6 mice aged 10–12 weeks with EAE | Significant improvement and delay of EAE symptoms. Significant decrease in the extent of demyelination. Significant reduction in the expression levels of TNF-α, IFN-γ, and Bax, and increase of levels of TGF-β and Bcl2 and the activity of Gpx1. |
| Ursolic acid (pentacyclic triterpenoid compound) | Yamamoto et al., 2020 [251] | Male C57BL/6J mice with cuprizone-induced demyelination | Significant improvement in motor dysfunction and demyelination. Increase of IGF-1 levels in the demyelinating lesions. |
| Herbal extract of Melilotus officinalis | Hassani et al., 2020 [252] | Female C57BL/6 mice with EAE | Prevention or attenuation of the clinical signs of the disease. Decreased demyelination in the corpus callosum. Significant decrease in the gene expression of pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ). Increase in the gene expression of GPx and CAT. |
| Piperine, a main bioactive alkaloid of black pepper | Nasrnezhad et al., 2021 [253] | Female Lewis rats with EAE | Significant improvement in neurological deficits and progression. Significant decrease in the extent of demyelination, inflammation, immune cell infiltration, microglia, and astrocyte activation in the spinal cord. Significant decrease in the gene of pro-inflammatory cytokines (TNF-α, IL-1β) and iNOS and enhanced IL-10, Nrf2, HO-1, and MBP expressions. Increase in TAC and reduction of MDA levels in the CNS. Reduction of caspase-3 (apoptosis marker) and enhancement of brain-derived neurotrophic factor (BDNF) and NeuN-expressing cells in the CNS. |
| Diosgenin (herbal from Dioscora species) | Zeinali et al., 2021 [254] | Female C57BL/6 mice aged 10–12 weeks with EAE | Significant clinical improvement. Decrease of inflammation, demyelination, and axonal degeneration severity in lumbar spinal cord in EAE. Lack of effect on modification of neuroprotective factors decreased by EAE. Decrease in serum and tissue levels of TNFα and MMP-9 with no effect on increased level of IL-17 in EAE. |
| Withametelin (phytosterol derivative) | Khan et al., 2021 [255] | Female Swiss mice of 8–12 weeks of age with EAE | Significant clinical improvement. Reversion of histopathological alteration of the brain, spinal cord, eye, and optic nerve. Reduction of H2O2-induced cytotoxicity and oxidative stress in a dose-dependent manner. Increase in the expression level of nuclear factor-erythroid-related factor-2 (Nrf2), heme-oxygenase-1 (HO-1), and reduction of the expression level of the Kelch-like-ECH-associated-protein-1 (keap-1), inducible-nitric-oxide-synthase (iNOS) in the CNS. Decrease in the expression level of toll-like-receptor 4 (TLR4), nuclear-factor-kappa-B (NF-κB), and increase in the expression level of IkB-α in the CNS. |
| Memantine (uncompetitive NMDA receptor antagonist) | Dąbrowska-Bouta et al. 2021 [256] | Female Lewis rats with EAE | Significant clinical improvement. Significant decrease in MDA levels and SOD1 and SOD2 expression, and increase in –SH groups levels in brain tissue. |
| Tibolone (synthetic steroid whose metabolites have potent antioxidant action) | Mancino et al., 2022 [257] | Female C57BL/6 mice with EAE | Significant clinical improvement. Reversion of the astrocytic and microglial reaction and reduction of the hyperexpression of TLR4, HMGB1, and NLR family pyrin domain containing 3-caspase 1-interleukin-1β inflammasome activation in the spinal cord. Attenuation of the Akt/nuclear factor kappa B pathway and decrease in the white matter demyelination area in the spinal cord. |
| Herbal plants Nepeta hindustana L., Vitex negundo L., and Argemone albiflora L. | Rasool et al., 2022 [258] | Wistar rats with lipopolysaccharide-induced MS | Neuroprotective effect regarding remyelination of axonal terminals and oligodendrocytes migration reduced lymphocytic infiltrations and reduced necrosis of Purkinje cells in histopathological examination. Reverse of changes in serum levels of inflammatory markers (MMP-6, TNF-α, AOPPs, AGEs, NO, IL-17 and IL-2), MDA, antioxidant (SOD, GSH, CAT, GPx), DNA damage markers (Isop-2α, 8OHdG), RAGE, caspase-8, and p38, induced by lipopolysaccharides. |
| Acetyl-11-keto-β-boswellic acid (a major component of Boswellia serrata) | Nadeem et al., 2022 [259] | Female SJL/J mice 8–9 weeks old with EAE | Significant clinical improvement. Downregulation of inflammatory markers in CD11c + DCs (p-NF-κB, iNOS, and nitrotyrosine) and CNS (p-NF-κB, iNOS, nitrotyrosine, lipid peroxides, and total antioxidant capacity). |
| Acetyl-11-keto-β-boswellic acid (a major component of Boswellia serrata) | Upadhayay et al., 2022 [260] | Wistar rats with EAE | Significant improvement in clinical parameters improvement and reversion of the EAE-induced histopathological changes in the brain. Reversal of the decreased Nrf2 and HO-1 levels in the CSF and brain homogenate caused by EAE-induction. Decrease in caspase-3 and Bax, and increased Bcl-2 Levels in brain homogenates. Reversion of decrease in acetylcholine, dopamine, and serotonin, and increase in glutamate in brain homogenates induced by EAE. Reversion of the increase in AchE, MDA, and nitrite levels and reduction of GSH, SOD, and catalase levels induced by EAE. Decrease in TNF-αand IL-1β levels in brain homogenates. |
| Urtica dioica extract | Namazi et al., 2022 [261] | Male C57BL/6J mice 8 weeks old with cuprizone-induced demyelination | Significant decrease of demyelination with high doses. Significant decrease of MDA and HSP-70 brain levels with no effect on HSP-60. |
| Nebivolol | Naeem et al., 2022 [262] | Male C57BL/6J mice with cuprizone-induced demyelination | Significant clinical improvement and reversion of the EAE-induced histopathological changes. Modulation of microglial activation status by suppressing M1 markers (Iba-1, CD86, iNOS, NO, and TNF-α) and increasing M2 markers (Arg-1 and IL-10). Inhibition of NLRP3/caspase-1/IL-18 inflammatory cascade. Decrease of MDA levels and increase of CAT and SOD activities. |
| IM253 (herbal compound) | Esmaeilzadeh et al., 2022 [263] | Female C57Bl/6 mice 10–12 weeks old with EAE | Significant clinical improvement and delay of symptoms of EAE. Significant decrease in inflammation and demyelination. Significant reduction in the expression of pro-inflammatory cytokine coding genes (IL-6, TNF-α, IFN-γ, and IL-17) and increase in the expression of anti-inflammatory and anti-oxidant enzyme coding genes (TGF-β, GPX-1, and CAT) and TAC. |
| Zingiber officinale (ginger) extract | Moradi et al., 2022 [264] | Male Wistar rats 8-week old with cuprizone-induced demyelination | Significant clinical improvement and decrease of demyelination with high doses. Significant expression and increased levels of MBP and OLIG2. |
| Ginger extract | Kamankesh et al. 2023 [265] | Female C57Bl/6 mice 8 weeks old with EAE | Significant clinical improvement without a decrease in lymphocyte infiltration. Reduction of gene expression levels of the inflammatory cytokines IL-17 and IFN-γ. Significant increase of Treg cells. Significant reduction of serum NO levels. |
| Grape seed extract | Mabrouk et al., 2022 [266] | Female C57Bl/6 mice 6 weeks old with EAE | Significant clinical improvement and decrease of demyelination induced by EAE. Significant decrease in MDA and carbonyl protein levels, increase in SOD1, SOD2, GPx, and CAT activities, decrease in GFAP expression, and increase in SIRT1 expression in the brain and spinal cord (reversing the effects of EAE). |
| Grape Seed Extract | Wang et al., 2023 [267] | C57BL/6 mice with EAE | Significant improvement of clinical symptoms of EAE. Inhibition of spinal cord demyelination and inflammatory cell infiltration. Inhibition of the secretion of TNF-α, IL-1 β, IL-6, IL-12, IL-17, and IFN-γ cells and reduction of the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors in the spleen. Inhibition of the infiltration of CD45+CD11b+ and CD45+CD4+ cells, differentiation of Th1 and Th17 (p < 0.05), reduction of secretion of inflammatory factors, and prevented the activation of microglia in the CNS. |
| Daphnetin (7,8-dihydroxy-coumarin) | Soltanmoham-madi et al., 2022 [268] | Female C57Bl/6 mice 8 weeks old with EAE | Significant clinical improvement and decrease of demyelination and lymphocyte infiltration in the CNS. Increase in the expression of anti-inflammatory cytokines and transcription factors (IL-4, IL-10, IL-33, GATA3, TGF-β, FoxP3), and reduction in the production of pro-inflammatory cytokines and transcription factors (IFN-γ, STAT4, T-bet, IL-17, STAT3, ROR-γt, TNF-α) in the CNS. Significant increase of the ratio of spleen Treg cells and the levels of IL-4, IL-10, TGF-β, and IL-33, and reduction of the levels of IFN-γ, TNF-α, and IL-17 in splenocytes. |
| Gallic (3,4,5-tri hydroxybenzoic) acid | Stegnjaić et al., 2022 [269] | Dark Agouti (DA) rats 5–7 months old with EAE | Significant clinical improvement and decrease of demyelination and lymphocyte infiltration in the CNS. Decrease in the release of IL-17, IFN-γ, and NO, decrease in the proportion of OX40+ or CD25+ CD4+ and Th17 cells in the spinal cord. Inhibition of NO, IL-6, and TNF release from macrophages and microglia. |
| Enterococcus durans (probiotic) | Samani et al., 2022 [270] | Female C57Bl/6 mice 8–10 weeks old with EAE | Significant decrease of demyelination and lymphocyte infiltration in the CNS. Significant decrease of the inflammatory cytokines IL-17, IFN-γ, and MMP-9, and increase in the MBP levels at the spinal cord |
| Ilepcimide (antiepilepsirine) | Xu et al., 2023 [271] | Female C57Bl/6 mice 8–10 weeks old with EAE | Ameliorates demyelination, blood–brain barrier leakage, and infiltration of CD4+ and CD8+ T cells. |
| Cannabigerol (phytocannabinoid) | Feinshtein et al., 2023 [272] | Female C57Bl/6 mice 8 weeks old with EAE | Significant clinical improvement. Reversion of enhanced neuronal loss and areas stained for GFAP in the spinal cord. |
| L-Theanine (antioxidant present in green tea) | Khosravi-Nezhad et al., 2023 [273] | Female C57Bl/6 mice 4–6 weeks old with cuprizone-induced demyelination | Significant clinical improvement. Reversion of the increase of MDA and the decrease in SOD, GPx, and TAC serum levels induced by cuprizone. |
| Vitamin D | Haindl et al., 2023 [274] | Male Dark Agouti rats aged 10–12 weeks with EAE | Significant reduction in myelin loss, microglial activation, and number of apoptotic cells. Significant reduction of seri, levels of oxidized lipid markers and NfL, and increase in serum TAC and protective polyphenols. |
| Peroxiredoxin 6 | Lunin et al., 2023 [275] | Female SJL/J mice, aged 3 months | Significant clinical improvement. Decrease of EAE-induced NOX1 and NOX4 gene expression in brain tissue |
| Bifidobacterium breve and Lactobacillus casei (probiotics) | Hasaniani et al., 2023 [276] | Male Wistar rats aged 5–6 weeks with cuprizone-induced demyelination | Significant clinical improvement. Increase in HO-1 and Nrf-2 gene expression, reduction of MDA levels, and increase in TAC in demyelinated corpus callosum. |
| Sinomenine (isoquinoline alkaloid isolated from Sinomenii acutum) | Fan et al., 2023 [277] | C57Bl/6 mice 8 weeks old with EAE | Significant amelioration of EAE severity. Reduction in the demyelination, axonal damage, and inhibition of inflammatory cell infiltration in the spinal cord. Decrease in the inflammatory cytokines TNF-α and IL-1β, MCP-1, and GM-CSF expression in the spinal cord and serum, increase in anti-inflammatory cytokine IL-10 expression in the spinal cord, and suppression of microglia and astrocytes activation in EAE mice. Inhibition of oxidative stress (reduction in MDA and advanced oxidation protein products (AOPP) levels in the spinal cord) via the activation of the Nrf2 signaling pathway (increase in expression of HO-1, NQO-1, and Nrf2 expression in the spinal cord. Suppression of lipopolysaccharide (LPS)-induced microglial activation and the production of pro-inflammatory factors in vitro. |
| Auranofin (thiol-reactive gold-containing compound) | Al-Kharashi et al., 2023 [278] | Female SJL/J mice aged 9–10 weeks with EAE | Significant amelioration of the clinical features. Increase in thioredoxin reductase (TrxR) activity, decrease in Nrf2 signaling, downregulation of the p-NFkB, decrease of iNOS mRNA expression, IL-6 mRNA levels, lipid peroxides levels, and myeloperoxidase activity in the brain and Peripheral Myeloid Immune Cells. |
| Vanillic acid | Safwat et al., 2023 [279] | Male Sprague–Dawley 12–16 weeks with cuprizone-induced demyelination | Significant improvement in alterations of nerve conduction velocity and demyelination deterioration of the sciatic nerve fibers induced by cuprizone. Significant improvement of the increase in IL1-7 level, expression of INF-γ and caspase-3, and the reduction in the expression of MBP, Nrf2, and HO-1 induced by cuprizone in the sciatic nerve. |
| Docosahexaenoic acid | Muñoz-Jurado et al., 2024 [280] | Male Dark Agouti rats with EAE | Significant clinical improvement. Decrease in lipid peroxides, carbonylated proteins, nitric oxide, and GSSG, and reduction of GSH levels in brain, spinal cord, blood, and various tissues. |
| Nicorandil (ATP-sensitive potassium channels opener) + carvedilol (α and β adrenoceptor antagonist) | Mustafa et al., 2024 [281] | Male Sprague–Dawley rats with EAE | Significant clinical improvement. Significant improvement of demyelination. Downregulation of TLR4/MYD88/TRAF6 signaling cascade with inhibition of (pT183/Y185)-JNK/p38 (pT180/Y182)-MAPK axis with reduction of IL-1β, IL-6NF-κB, and TNF-α in the brain. Increase of SOD activity and Nrf2 content and reduction of MDA content of the brain. Inhibition of gene expression for CD4, IL-17, IL-23, and TGF-β. Anti-apoptotic effect by decreasing Bax protein expression and caspase-3 content and increasing Bcl-2. |
| Purmorphamine (Smo-Shh/Gli activator) | Prajapati et al., 2024 [282] | Wistar rats of both sexes with EAE | Significant improvement of clinical parameters and histological changes Significant decrease in the levels of Smo-Shh in brain homogenate, blood plasma, and cerebrospinal fluid. Decrease of brain and plasma TNF-α and IL-1β levels. Decrease of MDA, nitrite, and AchE and increase of reduced glutathione, SOD, and CAT brain levels. Reversion of the increase in the apoptosis-related markers caspase-3 and Bax and the decrease of Bcl-2 anti-apoptotic protein induced by EAE in the brain and plasma. Reversion of the increased neurofilament protein levels in the brain. Increased brain levels of acetylcholine, dopamine, and serotonin and decrease of glutamate. |
| Arbutin (glycosylated derivative of hydroquinone present in the leaves and bark of bearberry and other plants) | Ashrafpour et al., 2024 [283] | Adult male Wistar rats with demyelination induced by injection of lysolecithin into the hippocampus | Significant improvement of memory impairment. Reduction of demyelination and astrocyte activation, and increase of MBP. Suppression of pro-inflammatory markers (IL-1β, TNF-α) and increase of anti-inflammatory cytokine IL-10. Decreased iNOS and increase of anti-oxidative factors (Nrf2, HO-1) and BDNF expression. |
| Cerium oxide nanoparticles | Nguyen et al., 2024 [284] | Female BALB/c mice aged 6–8 weeks and female C57BL/6 mice aged 9–10 weeks with EAE | Significant clinical improvement. Reversion of the increase in expression of T cells, dendritic cells, and resident microglia in the CNS and in IFN-γ expression among CD4+ T cells sampled from spleen tissue induced by EAE. Reduction in demyelination in the spinal cord. |