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Effect of GA on the kinetic properties of sEPSC during the course of EAE. a EAE-GA MSNs showed reduced half width and decay time compared to EAE-vehicle at 21 – 25 dpi (decay time:* p <0.05 EAE-GA vs EAE-vehicle, #p p <0.05 EAE-vehicle vs CFA- vehicle; half width: ** p <0.01 EAE-GA vs EAE-vehicle, ##p p <0.01 EAE-vehicle vs CFA-vehicle), while no effect by GA could be observed on both rise time and amplitude ( p >0.05). The electrophysiological traces on the bottom are examples of sEPSCs recorded from MSNs of CFA-vehicle, EAE-vehicle and EAE-GA mice. b the beneficial role of GA is maintained in the chronic phase of the disease (50 dpi), as observed by restored half width and decay time (** p <0.01 EAE-GA vs EAE-vehicle and ## p <0.01 EAE-vehicle vs CFA-vehicle for both the parameters)
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Glutamate-mediated excitotoxicity is supposed to induce neurodegeneration in multiple sclerosis (MS). Glatiramer acetate (GA) is an immunomodulatory agent used in MS treatment with potential neuroprotective action. Aim of the present study was to investigate whether GA has effects on glutamate transmission alterations occurring in experimental auto...
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Context 1
... EAE mice receiving only vehicle (4 mice per group; decay time: CFA- vehicle 3.22±0.31 ms n=8, EAE-vehicle 4.02±0.18 ms n= 12, EAE-GA 3.18±0.2 ms n=10; Tukey's post hoc analysis p<0.05 EAE-GA vs EAE-vehicle; half width: CFA-vehicle 4.0±0.22 ms, EAE-vehicle 5.84±0.26 ms, EAE-GA 4.32± 0.23 ms; Tukey's post hoc analysis p<0.01 EAE-GA vs EAE-vehicle) (Fig. 1a). Both amplitude and rise time, pre- viously found unchanged in EAE ( Centonze et al. 2009), were not affected by GA treatment (amplitude: CFA-vehicle 10.55±0.42 pA, EAE-vehicle 10.68±0.54 pA, EAE-GA 10.45 ± 0.45 pA, one-way ANOVA p > 0.05; rise time: CFA-vehicle 0.99±0.08 ms, EAE-vehicle 0.85±0.09 ms, EAE-GA 0.95 ± 0.06 ms, one-way ...
Context 2
... Both amplitude and rise time, pre- viously found unchanged in EAE ( Centonze et al. 2009), were not affected by GA treatment (amplitude: CFA-vehicle 10.55±0.42 pA, EAE-vehicle 10.68±0.54 pA, EAE-GA 10.45 ± 0.45 pA, one-way ANOVA p > 0.05; rise time: CFA-vehicle 0.99±0.08 ms, EAE-vehicle 0.85±0.09 ms, EAE-GA 0.95 ± 0.06 ms, one-way ANOVA p > 0.05) (Fig. ...
Context 3
... sEPSCs observed in EAE-vehicle striatum (4 mice; decay time: CFA-vehicle 3.42±0.15 ms n=12, EAE- vehicle 5.16±0.18 ms n=10, EAE-GA 3.27±0.2 ms n=13, Tukey's post hoc analysis p<0.01 EAE-GA vs EAE-vehicle; half width: CFA-vehicle 4.08±0.19 ms, EAE-vehicle 6.24± 0.26 ms, EAE-GA 3.81±0.23 ms; Tukey's post hoc analysis p<0.01 EAE-GA vs EAE-vehicle) (Fig. 1b). Amplitude and rise time were still unchanged respect to CFA-vehicle (ampli- tude: CFA-vehicle 10.65±0.42 pA, EAE-vehicle 10.82±0.54 pA, EAE-GA 11.05±0.55 pA, one-way ANOVA p>0.05; rise time: CFA-vehicle 1.08 ± 0.07 ms, EAE-vehicle 1.10 ± 0.08 ms, EAE-GA 0.93±0.06 ms, one-way ANOVA ...
Context 4
... positive cells inside the striatum, shows the effect of GA in reducing microglial hypertropy observed in EAE-vehicle, expressed as mean cell area (c) and total microglial area (d). Data are expressed as mean ± S.E.M. Tukey's post hoc test: EAE- GA vs EAE-vehicle **p<0.01, ***p<0.001, EAE-vehicle vs CFA- vehicle ## p<0.01, ### p<0.001 vehicle mice (Fig. 4a: Iba1 red fluorescence, nuclei stained with dapi in blue). As expected, in acute phase EAE-vehicle there is a substantial increase in the number of microglial cells per area (density) compared to control CFA-vehicle, due to proliferation (Centonze et al. 2009), a process which starts in the presymptomatic phase of the disease (7 dpi) ( Haji ...
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Citations
... The decrease in glutamate concentration in the CSF may also be linked to the ability of GA to reduce immune cells infiltration, as well as its ability to reduce microglial and astrocyte activation [10,35,52]. It has been reported that GA affects glutamate transmission alterations in the nucleus striatum of EAE mice by attenuating microglial activation [53]. The novel effect found in the current study, namely elimination of interstitial glutamate excess, may play a role in reducing excitotoxic neuronal and oligodendrocyte cell death, thus reducing CNS tissue damage. ...
Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35–55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.
... Moreover, the density of cells positive for the pro-inflammatory microglia markers integrin alpha-M precursor (MAC-1/ITGAM) and galectin-3 (MAC-2) was decreased in PLP-and MOG-induced EAE mice [164][165][166] and in a double-transgenic (APP/Presenilin-1; PS1) mouse AD model [167]. In addition, the morphological transformation of ramified resting microglia into a pro-inflammatory amoeboid morphology was attenuated in vitro by GA in human primary fetal and adult microglia activated by T-lymphocytes [168] and in EAE-mouse slice cultures [169]. In contrast, the number of IBA1-positive microglia increased in the hippocampus of a rat model of cranial irradiation-induced brain injury [162] and GA-treated cuprizone mice showed an expansion of MAC-1 and CD68-positive M1 microglia numbers [170]. ...
... More consistent evidence towards a shift from a pro-inflammatory to an anti-inflammatory phenotype has been provided through studies analyzing the cytokines secreted by M1 pro-inflammatory microglia following treatment with GA. For example, a decrease in TNFα secretion was found after the GA treatment of BV-2 microglia cells [169], in IBA1-positive cells in EAE-mouse slice cultures [169], in primary rat microglia cultures [171], and in human fetal and adult microglia activated by T-lymphocytes [168]. In line with this, the migration of GA-exposed T-cells into the brains of EAE mice resulted in the increased expression of the anti-inflammatory microglial markers IL-10 and transforming growth factor-beta 2 (TGF-β2) [174], but the GA-treated co-cultures of microglia and activated T-lymphocytes showed a reduction of IL-10 [168]. ...
... More consistent evidence towards a shift from a pro-inflammatory to an anti-inflammatory phenotype has been provided through studies analyzing the cytokines secreted by M1 pro-inflammatory microglia following treatment with GA. For example, a decrease in TNFα secretion was found after the GA treatment of BV-2 microglia cells [169], in IBA1-positive cells in EAE-mouse slice cultures [169], in primary rat microglia cultures [171], and in human fetal and adult microglia activated by T-lymphocytes [168]. In line with this, the migration of GA-exposed T-cells into the brains of EAE mice resulted in the increased expression of the anti-inflammatory microglial markers IL-10 and transforming growth factor-beta 2 (TGF-β2) [174], but the GA-treated co-cultures of microglia and activated T-lymphocytes showed a reduction of IL-10 [168]. ...
Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.
... Now, both white matter and gray matter pathologies are recognized as hallmarks of the disease. Cortical and deep matter demyelination can appear independently of white matter demyelination, and neurodegenerative processes are not merely a consequence of a white matter damage but has been related to meningeal infiltrates that in turn induces neuroinflammation and neuronal and synaptic damages [4]. ...
Introduction: It has been recognized for about 20 years that interleukin (IL)-1 signaling is implicated in Multiple Sclerosis (MS), a disabling, chronic, inflammatory and neurodegenerative disease of the central nervous system (CNS). Only recently, multifaceted roles of IL-1 emerged in MS pathophysiology as a result of both clinical and preclinical studies. Notably, drugs that directly target the IL-1 system have not been tested so far in MS.
Areas covered: Recent studies in animal models, together with the development of ex vivo chimeric MS models, have disclosed a critical role for IL-1 not only at the peripheral level but also within the CNS. In the present review, we highlight the IL-1-dependent neuropathological aspects of MS, by providing an overview of the cells of the immune and CNS systems that respond to IL-1 signaling, and by emphasizing the subsequent effects on the CNS, from demyelinating processes, to synaptopathy, and excitotoxicity.
Expert opinion: Drugs that act on the IL-1 system show a therapeutic potential in several autoinflammatory diseases and preclinical studies have highlighted the effects of these compounds in MS. We will discuss why anti-IL-1 therapies in MS have been neglected to date.
... vivo experiments consisting of the incubation of EAE T cells with murine brain slices of healthy mice revealed the synaptotoxic effect of T cells on glutamatergic transmission [5][6][7]. ...
... Mice were sacrificed by cervical dislocation and the brains were removed. Then, corticostriatal coronal slices (200 μm) were cut by means of a Vibratome (Leica VT1200) [5,6]. A single slice was then transferred to a recording chamber and submerged in a Picrotoxin (50 μM) was added to the perfusing solution to block GABA A -mediated transmission. ...
Aims
The crucial step in the pathogenic events that lead to the development and the progression of Multiple Sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate‐mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients.
Methods
A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and non‐active (na) relapsing remitting (RR) MS patients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells.
Results
Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase of glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects.
Conclusion
These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF‐mediated mechanisms of glutamate excitotoxicity in central neurons.
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... These changes were partially dependent on the activation of microglia by a Th1 cytokine profile. Also, GA decreased the density of microglia and its surface, measures indicative of activation, as well as the amount of TNFα in these cells(Gentile et al., 2013).---PlaceFigure 1around here ---Excitotoxicity results not only from excessive glutamatergic neurotransmission, but also from insufficient inhibitory inputs to counterbalance excitatory signals. ...
Multiple sclerosis-related neurobehavioral abnormalities are one of the main components of disability in this disease. The same pathological processes that explain demyelination periods and neurodegeneration also allow the comprehension of neurobehavioral abnormalities. Inflammation in the central nervous system caused by cells of the immune system, especially lymphocytes, and by resident cells, such as astrocytes and microglia, directly modulate neurotransmission and synaptic physiology, resulting in behavioral changes (such as sickness behavior) and amplifying the degenerative mechanisms that occur in multiple sclerosis. In addition, neuronal death caused by glutamate-mediated excitotoxicity, alterations in GABAergic, serotonergic, and dopaminergic neurotransmission, and the mechanisms of axon damage are of foremost importance to explain the reduction in brain volume and the associated cognitive decline. Neuroinflammation and neurodegeneration are not isolated phenomena and various instances of interaction between them have been described. This presents attractive targets for the development of therapeutic strategies for this neglected component of multiple sclerosis related disability.
... Quite interestingly, the abovementioned therapeutics were also described to ameliorate glutamatergic synaptic transmission (152)(153)(154)(155) further supporting the strict connection linking CCL5 overexpression and glutamatergic synaptic derangements. ...
The immune system (IS) and the central nervous system (CNS) are functionally coupled, and a large number of endogenous molecules (i.e., the chemokines for the IS and the classic neurotransmitters for the CNS) are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years, evidence has been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre- and/or post-synaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous pro-inflammatory factor released by glial cells, i.e., the chemokine Regulated upon Activation Normal T-cell Expressed and Secreted (CCL5) and the principal neurotransmitter in CNS (i.e., glutamate) in physiological and pathological conditions. In particular, the review discusses preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of multiple sclerosis (MS), but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease-modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature.
... After it was shown that, instead of promoting, it suppressed EAE [4], this molecule was explored for its possible therapeutic effect, although its mechanism of action is still not fully known [2]. GA's mechanism of action encompasses both anti-inflammatory properties (such as promoting a shift toward a Th2 pattern for reactive T cells, reducing production of inflammatory cytokines and enhancing T regulatory cells and anti-inflammatory cytokines [5][6][7][8]) as well as neuroprotective properties (such as increasing levels of neurotrophic factors, favoring axonal protection and possibly reducing glutamate-mediated neurotoxicity [9][10][11]). Among biological characteristics of GA, its immunogenicity needs to be highlighted for the purposes of this review: in a high proportion of patients treated with GA a low but significant titer of anti-GA antibodies (anti-GA) is produced [12]. ...
... The GATE study is a randomized, double blind active and placebo-controlled equivalence trial conducted in 17 countries in 2011-2013 and published in 2015. Patients included were naïve to GA, had mild to moderate disability [Expanded Disability Status Scale (EDSS) [33] of 0-5.5], and had an active disease (a relapse in the previous year, and [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Gd? lesions at the screening scan). A total of 796 patients were randomized to either Copemyl 20, GA, or placebo, with a ratio of 4.3:4.3:1. ...
Economic sustainability is of paramount importance in the rapidly evolving therapeutic scenario of multiple sclerosis (MS). Glatiramoids are a class of drugs whose forefather, glatiramer acetate, has been used as a disease modifying drug (DMD) in patients with MS for over 20 years. Its patent expired in 2015; new versions of such drug are nowadays available on the market, potentially contributing to lowering prices and enhancing a better allocation of economic resources. In this review, we analyze the recommendations underlying the approval of both generic drugs and biosimilars by regulatory authorities, and we provide methodological tools to contextualize the design of studies on these new classes of drugs. We examine in more detail the preclinical and clinical data of Copemyl®, a new member of the glatiramoid class, focusing on its biological and immunological properties and illustrating randomized controlled trials that led to its authorization.
... Part 7B: Some of the current treatments for MS affect the glutamatergic pathway Study 1 Glatiramer acetate -COPAXONEÒan immunomodulator drug for MS-has neuroprotective effects against glutamate toxicity Gentile et al. (2013) investigated whether Glatiramer acetate (GA), a drug for MS, has effects on glutamate transmission alterations occurring in EAE, and found that it protects against inflammatory synaptopathy in EAE. In further detail, single neuron electrophysiological recordings and immunofluorescence analysis of microglia activation were performed in the striatum of EAE mice, treated or not with GA, at different stages of the disease. ...
Glutamate is the major excitatory neurotransmitter in the nervous system, where it induces multiple beneficial and essential effects. Yet, excess glutamate, evident in a kaleidoscope of acute and chronic pathologies, is absolutely catastrophic, since it induces excitotoxicity and massive loss of brain function. Both the beneficial and the detrimental effects of glutamate are mediated by a large family of glutamate receptors (GluRs): the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs), expressed by most/all cells of the nervous system, and also by many non-neural cells in various peripheral organs and tissues. T cells express on their cell surface several types of functional GluRs, and so do few other immune cells. Furthermore, glutamate by itself activates resting normal human T cells, and induces/elevates key T cell functions, among them: T cell adhesion, chemotactic migration, cytokine secretion, gene expression and more. Glutamate has also potent effects on antigen/mitogen/cytokine-activated T cells. Furthermore, T cells can even produce and release glutamate, and affect other cells and themselves via their own glutamate. Multiple sclerosis (MS) and its animal model Experimental Autoimmune Encephalomyelitis (EAE) are mediated by autoimmune T cells. In MS and EAE, there are excess glutamate levels, and multiple abnormalities in glutamate degrading enzymes, glutamate transporters, glutamate receptors and glutamate signaling. Some GluR antagonists block EAE. Enhancer of mGluR4 protects from EAE via regulatory T cells (Tregs), while mGluR4 deficiency exacerbates EAE. The protective effect of mGluR4 on EAE calls for testing GluR4 enhancers in MS patients. Oral MS therapeutics, namely Fingolimod, dimethyl fumarate and their respective metabolites Fingolimod-phosphate and monomethyl fumarate, can protect neurons against acute glutamatergic excitotoxic damage. Furthermore, Fingolimod reduce glutamate-mediated intracortical excitability in relapsing–remitting MS. Glatiramer acetate -COPAXONE®, an immunomodulator drug for MS, reverses TNF-α-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents in EAE-afflicted mice. With regard to T cells of MS patients: (1) The cell surface expression of a specific GluR: the AMPA GluR3 is elevated in T cells of MS patients during relapse and with active disease, (2) Glutamate and AMPA (a selective agonist for glutamate/AMPA iGluRs) augment chemotactic migration of T cells of MS patients, (3) Glutamate augments proliferation of T cells of MS patients in response to myelin-derived proteins: MBP and MOG, (4) T cells of MS patients respond abnormally to glutamate, (5) Significantly higher proliferation values in response to glutamate were found in MS patients assessed during relapse, and in those with gadolinium (Gd)+ enhancing lesions on MRI. Furthermore, glutamate released from autoreactive T cells induces excitotoxic cell death of neurons. Taken together, the evidences accumulated thus far indicate that abnormal glutamate levels and signaling in the nervous system, direct activation of T cells by glutamate, and glutamate release by T cells, can all contribute to MS. This may be true also to other neurological diseases. It is postulated herein that the detrimental activation of autoimmune T cells by glutamate in MS could lead to: (1) Cytotoxicity in the CNS: T cell-mediated killing of neurons and glia cells, which would subsequently increase the extracellular glutamate levels, and by doing so increase the excitotoxicity mediated by excess glutamate, (2) Release of proinflammatory cytokines, e.g., TNFα and IFNγ that increase neuroinflammation. Finally, if excess glutamate, abnormal neuronal signaling, glutamate-induced activation of T cells, and glutamate release by T cells are indeed all playing a key detrimental role in MS, then optional therapeutic tolls include GluR antagonists, although these may have various side effects. In addition, an especially attractive therapeutic strategy is the novel and entirely different therapeutic approach to minimize excess glutamate and excitotoxicity, titled: ‘brain to blood glutamate scavenging’, designed to lower excess glutamate levels in the CNS by ‘pumping it out’ from the brain to the blood. The glutamate scavanging is achieved by lowering glutamate levels in the blood by intravenous injection of the blood enzyme glutamate oxaloacetate transaminase (GOT). The glutamate-scavenging technology, which is still experimental, validated so far for other brain pathologies, but not tested on MS or EAE yet, may be beneficial for MS too, since it could decrease both the deleterious effects of excess glutamate on neural cells, and the activation of autoimmune T cells by glutamate in the brain. The topic of glutamate scavenging, and also its potential benefit for MS, are discussed towards the end of the review, and call for research in this direction.
... Furthermore, GA has been proven to be neuroprotective against glutamate toxicity [96] and has an influence on the stability of nerve terminals [97]. Some of the recent studies applying the use of Copaxone ® in several inflammatory diseases are presented in Table 2. ...
Parkinson's Disease (PD) is the second most common neurodegenerative disease in the world, however, there is no cure for it. Current treatments only relieve some of the symptoms, without ceasing the disease, and lose efficacy with prolonged treatment. Considerable evidence shows that persistent inflammatory responses, involving T cell infiltration and glial cell activation, are common characteristics of human patients and play a crucial role in the degeneration of dopaminergic neurons. Therefore, it is important to develop therapeutic strategies that can impede or halt the disease through the modulation of the peripheral immune system by aiming at controlling the existing neuroinflammation. Most of the immunomodulatory therapies designed for the treatment of Parkinson's Disease are based on vaccines using AS or antibodies against it; yet, it is of significant interest to explore other formulations that could be used as therapeutic agents. Several vaccination procedures have shown that inducing regulatory T cells in the periphery is protective in PD animal models. In this regard, the formulation glatiramer acetate (Copaxone(®) ), extensively used for the treatment of multiple sclerosis, could be a suitable candidate due to its capability to increase the number and suppressor capacity of regulatory T cells. In this review, we will present some of the recent immunomodulatory therapies for PD including vaccinations with AS or glatiramoids, or both, as treatments of PD pathology. This article is protected by copyright. All rights reserved.
... Several protocols using two-photon imaging or electrophysiological recordings were described. These studies compared control and EAE slices [309][310][311] and could be used to evaluate the direct effects of potential therapeutics [312]. Recently, techniques of in vivo monitoring of inflammatory diseases like EAE evolved [313][314][315]. ...
... Halts egress from the lymph nodes [347]; limits DCs migration to the CNS [356] Reduces reactive astrogliosis [354]; provokes production of neurothrophic factor [357,358] Enhances neurotrophic factors production, antiinflammatory effects [363] Acts protectively [347] DMF (Tecfidera ® ) Antioxidative effects in immune cells [364]; antiinflammatory effects in DC [371] Reduces IL-6 levels, increases glutathione and HO-1 [367,368] Promotes anti-inflammatory and antioxidative effects [369,370] Alters antioxidant and lipid metabolism thus promoting myelin preservation [366] GA (Copaxone) Modulation of T cell activation and proliferation [326,327] Elevates production of neurotrophic factors [330] Acts anti-proliferative and anti-inflammatory [312,331,332] Promotes oligodendrogenesis and remyelination [328,329] IFN-β Inhibits T cell activation, adhesion to BBB, maintains DC homeostasis [317,323,324] Acts antioxidative and antiinflammatory [319,320,321] Laquinimod Downregulates immunogenicity of dendritic cell responses [375] Acts anti-inflammatory [377] Inhibits activation and reduces NO induced neurotoxicity [378] Prevents demyelination [376] Mitoxantrone Modulates B and T cell proliferation and activation ; induces apoptosis of DC [336] Suppresses astrocyte activation via reduction of NO and proinflammatory cytokines [334] Induces cell death by increasing IL10 production and suppresses activation [335] Natalizumab (Tysabri) ...
... GA decreases the production of pro-inflammatory mediators, like TNF expression; while in LPS stimulated BV-2 microglia it increases levels of anti-inflammatory IL-10 production [331]. Further, GA reduces proliferation and remodels activated microglia to acquire phenotype and the resting morphology in vivo [312]. The significant inhibition of microglial activation by GA was observed in MS patients [332]. ...
Persistent neuroinflammation is now recognized as a chief pathological component of practically all neurodegenerative diseases. Neuroinflammation in the central nervous system (CNS), is accompanied with immune responses of glial cells. Glial cells respond to pathological stimuli through antigen presentation, and cytokine and chemokine signaling. Therefore, limiting CNS inflammation represents prospective therapeutic approach in diseases like Alzheimer's, amyotrophic lateral sclerosis, Parkinson's, ischemia, various psychiatric disorders and Multiple sclerosis (MS). As a complex disease, MS is characterized by neuroinflamation, demyelination and sequential axonal loss. Due to unknown etiology and the heterogeneous presentation of the disease, MS is hard to treat and the search for potential therapeutics is wide and meticulous. However, finding a proper anti-neuroinflammatory drug may bring an advance in selecting noveltreatment regimens of ample of neurodegenerative diseases and neurological disorders. The present review gives the overview of the existing and potential therapies in MS, aimed to modulate neuroinflammation and ensure neuroprotection.
