Effectiveness of Amantadine in Reducing Relapses in Multiple Sclerosis

Plaut, G.S.

doi:10.1177/014107688708000210

Cited by 38 publications

(17 citation statements)

References 27 publications

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“…[3][4][5][6] These data are consistent with in vivo observations showing that imbalanced glutamate homeostasis contributes to neuronal and oligodendroglial pathology in MS 3,4,7 and that blockade of glutamate receptors ameliorates the clinical course of both MS 8 and EAE. 6,9,10 Among soluble mediators of inflammation, proinflammatory cytokines-such as tumor necrosis factor-a (TNFa) and interleukin-1b (IL-1b)-have gained attention owing to their propensity to enhance glutamate transmission in vitro, 6,[11][12][13] but their potential role in synaptic and neuronal alterations associated with MS is still elusive.…”

supporting

confidence: 78%

Interleukin‐1β causes synaptic hyperexcitability in multiple sclerosis

Rossi

Furlan

Chiara

et al. 2012

Annals of Neurology

187

182

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supporting

confidence: 78%

Interleukin‐1β causes synaptic hyperexcitability in multiple sclerosis

Rossi

Furlan

Chiara

et al. 2012

Annals of Neurology

187

182

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“…22 In addition, expressions of glutamate transporters are altered in MS [23][24][25] and in animal models of the disease, 26,27 and the loss of glutamate transporters in cortical lesions correlates with microglial activation and synaptic damage. 28 Finally, overactivation of glutamate receptors causes MS-like lesions, 29 whereas glutamate receptor antagonists exert beneficial effects in experimental autoimmune encephalomyelitis (EAE) [30][31][32][33] and in MS, 34 by limiting not only oligodendrocyte but also neuronal damage. 30,31,35 When administered at the onset of neurological deficits, various AMPA receptor antagonists (NBQX, MPQX, GYKI52466, GYKI53773) have been found to be capable of attenuating clinical decline, independently of any effect on CNS lymphocyte infiltration.…”

Section: Role Of Glutamate In Ms Neuronal Injurymentioning

confidence: 99%

The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis

Muzio²,

et al. 2009

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Multiple sclerosis (MS) has been classically regarded as a disorder of the white matter of the central nervous system (CNS). However, early alterations of the neuronal compartment occurring in this disorder are partially independent of demyelination. Soluble inflammatory cytokines and glutamate have been proposed as major determinants of neurodegeneration in MS as well as in its experimental animal model, namely experimental autoimmune encephalomyelitis (EAE). The relationship between these two major determinants has been largely elusive. In recent years, unexpected connections have emerged between immune cells and soluble cytokines on the one hand, and synaptic transmission and neurodegeneration on the other. Neurophysiological recordings have recently shown that glutamate-mediated excitatory postsynaptic currents are enhanced during the early phase of EAE, because of altered expression and phosphorylation of AMPA receptors and the downregulation of the immediate early gene Arc/Arg3.1. The synaptic alterations occurring during neuroinflammatory diseases are largely mediated by inflammatory cytokines released from infiltrating T cells and from activated microglia, and are responsible, at least in part, for irreversible dendritic pathology. Collectively, the data covered in this review article suggest that CNS-confined inflammation in MS is associated with the release of soluble molecules, which are capable of altering excitatory synaptic transmission and, finally, of stimulating secondary neurodegenerative gray matter pathology.

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“…In such brain areas of EAE mice, the excitatory glutamatergic transmission is potentiated, while the GABAergic inhibitory transmission is reduced: this imbalance in synaptic transmission leads to excitotoxicity and subsequently to neurodegeneration [11]. Of note, glutamate receptor antagonists and gamma-amino butyric acid (GABA) agonists exert beneficial effects in both EAE and MS [12–16]. This synaptopathy has been proposed as a valuable therapeutic target [11].…”

Section: Introductionmentioning

confidence: 99%

Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis

Gentile

Musella

Bullitta

et al. 2016

J Neuroinflammation

135

114

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BackgroundData from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target.Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE.MethodsMinipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells.ResultsSiponimod administration (0.45 μg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission.ConclusionsAltogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.

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Effectiveness of Amantadine in Reducing Relapses in Multiple Sclerosis

Cited by 38 publications

References 27 publications

Interleukin‐1β causes synaptic hyperexcitability in multiple sclerosis

Interleukin‐1β causes synaptic hyperexcitability in multiple sclerosis

The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis

Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis

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