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  • Multiple Sclerosis
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  • 1
    Language: English
    In: Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 05 January 2014, Vol.369(1633), pp.20130162
    Description: Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.
    Keywords: Experimental Autoimmune Encephalomyelitis ; Hippocampus ; Interleukin-1β ; Long-Term Potentiation ; Multiple Sclerosis ; Synaptic Plasticity ; Models, Neurological ; Cytokines -- Metabolism ; Encephalomyelitis, Autoimmune, Experimental -- Physiopathology ; Hippocampus -- Pathology ; Long-Term Potentiation -- Physiology ; Multiple Sclerosis -- Physiopathology ; Synapses -- Physiology
    ISSN: 09628436
    E-ISSN: 1471-2970
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  • 2
    Language: English
    In: European Journal of Pharmacology, 05 September 2018, Vol.834, pp.92-102
    Description: Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions.
    Keywords: Gasotransmitter ; Nitric Oxide ; Hydrogen Sulfide ; Carbon Monoxide ; Immune System ; Eae ; Neuroinflammation ; Multiple Sclerosis ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 3
    Language: English
    In: Neurological Sciences, 2011, Vol.31(Supplement 3), pp.283-288
    Description: Monoclonal antibodies, first introduced in cancer therapy and to prevent allograft rejection, represent new pharmacological tools for the treatment of autoimmune diseases. With the knowledge of immunological movements in autoimmunity, it is now possible to target each single step of the immune process, from the activation of T lymphocytes in lymph nodes to the formation of the immunological synapse, and to T cell differentiation and cytokine production. However, this approach is still not devoid of adverse effects. In fact, even if monoclonal antibodies exert selective immunomodulation by targeting only cells expressing a specific antigen, a widespread perturbation of the immune system is induced, leading to a predisposition for infections and infestations and to the occurrence of tumours.
    Keywords: Biological drugs ; Monoclonal antibodies ; Autoimmune diseases ; Multiple sclerosis
    ISSN: 1590-1874
    E-ISSN: 1590-3478
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  • 4
    In: Nature Medicine, 2010, Vol.16(8), p.897
    Description: High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper ([T.sub.H]17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling--which would normally decrease intracellular cAMP formation--biased [T.sub.H] cell commitment to the [T.sub.H]17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T ([T.sub.reg]) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.
    Keywords: Multiple Sclerosis -- Risk Factors ; Multiple Sclerosis -- Care And Treatment ; Multiple Sclerosis -- Research ; Neurotransmitter Receptors -- Physiological Aspects ; Neurotransmitter Receptors -- Research ; T Cells -- Physiological Aspects ; T Cells -- Research;
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(1), p.e54666
    Description: Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    In: Annals of Neurology, May 2013, Vol.73(5), pp.667-678
    Description: Objective The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. Methods We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1[beta]-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1[beta] sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation. Results We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. Interpretation Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders. Ann Neurol 2013; 73:667-678
    Keywords: Age ; Glutamic Acid Receptors (Metabotropic) ; Double Prime G Protein-Coupled Receptor Kinase 2 ; Brain Injury ; Neurological Diseases ; Multiple Sclerosis ; Alzheimer'S Disease ; Stroke ; Animal Models ; Neuroprotection ; Inflammation ; Neurodegenerative Diseases ; Cortex ; Beta -Adrenergic-Receptor Kinase ; Neonates ; Excitotoxicity ; Neurology & Neuropathology ; Natural Toxins;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 7
    Language: English
    In: Neurology and Therapy, 01 November 2018, Vol.7(2), pp.385-390
    Keywords: Equivalence ; Follow-on Glatiramer Acetate ; Glatiramer Acetate ; Multiple Sclerosis
    ISSN: 2193-8253
    E-ISSN: 2193-6536
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  • 8
    Language: English
    In: Drug Design, Development and Therapy, Annual, 2014, Vol.8, p.555(13)
    Description: New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood-brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism. Keywords: demyelinating diseases, pharmacotherapy, fingolimod, dimethyl fumarate, laquinimod, teriflunomide
    Keywords: Multiple Sclerosis -- Drug Therapy ; Multiple Sclerosis -- Research ; Fingolimod -- Health Aspects ; Fingolimod -- Research ; Dimethyl Fumarate -- Health Aspects ; Dimethyl Fumarate -- Research
    ISSN: 1177-8881
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  • 9
    Language: English
    In: Frontiers in Molecular Neuroscience, Nov 13, 2018
    Description: Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders.
    Keywords: Glutamate ; Nervous System Diseases
    ISSN: 1662-5099
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  • 10
    Language: English
    In: Frontiers in cellular neuroscience, 2014, Vol.8, pp.462
    Description: Group III metabotropic glutamate (mGlu) receptors mediate important neuroprotective and anti-inflammatory effects. Stimulation of mGlu4 receptor reduces neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) whereas mGlu4 knockout mice display exacerbated EAE clinical scores. We now show that mGlu4 receptors are expressed in oligodendrocytes, astrocytes and microglia in culture. Oligodendrocytes express mGlu4 receptors only at early stages of maturation (O4 positive), but not when more differentiated (myelin basic protein, MBP positive). Treatment of immature oligodendrocytes with the mGlu4 receptor agonist L-2-Amino-4-phosphonobutyrate (L-AP4; 50 μM for 48 h) accelerates differentiation with enhanced branching and earlier appearance of MBP staining. Oligodendrocyte death induced by exposure to 1 mM kainic acid for 24 h is significantly reduced by a 30-min pretreatment with L-AP4 (50 μM), an effect observed only in the presence of astrocytes, mimicked by the specific mGlu4 receptor positive allosteric modulator N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) (30 μM) and prevented by pretreatment with the mGlu4 receptor antagonist, cyclopropyl-4-phosphonophenylglycine (CPPG) (100 μM). In astrocytes, mGlu4 receptor is the most expressed among group III mGlu receptors, as by Quantitative real time PCR (QRT-PCR), and its silencing prevents protective effects. Protection is also observed when conditioned medium (CM) from L-AP4-pretreated astrocytes is transferred to oligodendrocytes challenged with kainic acid. Transforming growth factor β (TGF-β) mediates the increased oligodendrocyte survival as the effect of L-AP4 is mimicked by addition of 10 ng/ml TGF-β and prevented by incubation with a neutralizing anti-TGF-β antibody. In contrast, despite the expression of mGlu4 receptor in resting and activated microglia, CM from L-AP4-stimulated microglia does not modify kainate-induced oligodendrocyte toxicity. Our results suggest that mGlu4 receptors expressed in astrocytes mediate enhanced survival of oligodendrocytes under conditions of excitotoxicity.
    Keywords: Astrocytes ; Experimental Autoimmune Encephalomyelitis ; Multiple Sclerosis ; Oligodendrocytes ; Transforming Growth Factor Β
    ISSN: 1662-5102
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