Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration
Autor: | Gianvito Martino, Roberto Furlan, Gottardo De Angelis, Alessandra Bergami, Fabio Buttari, Giulia Maria Sancesario, Sergio Bernardini, Silvia Rossi, Valeria Studer, Diego Centonze, Francesca Barbieri, Caterina Motta |
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Přispěvatelé: | Rossi, S, Motta, C, Studer, V, Barbieri, F, Buttari, F, Bergami, A, Sancesario, G, Bernardini, S, De Angelis, G, Martino, Gianvito, Furlan, R, Centonze, D. |
Rok vydání: | 2013 |
Předmět: |
Adult
Male Pathology medicine.medical_specialty Multiple Sclerosis medicine.medical_treatment glutamate Inflammation cerebrospinal fluid synaptic transmission inflammation TNF-α B cells Proinflammatory cytokine Mice Young Adult Cerebrospinal fluid medicine Animals Humans Neurons Tumor Necrosis Factor-alpha business.industry Settore BIO/12 Multiple sclerosis Neurodegeneration Glutamate receptor Brain Excitatory Postsynaptic Potentials Middle Aged medicine.disease Cytokine Neurology Nerve Degeneration Female Settore MED/26 - Neurologia Tumor necrosis factor alpha Neurology (clinical) medicine.symptom business |
Zdroj: | Multiple Sclerosis Journal. 20:304-312 |
ISSN: | 1477-0970 1352-4585 |
Popis: | Background: Chronic inflammation leads to gray matter damage in progressive multiple sclerosis (MS), but the mechanism linking inflammation and neurodegeneration is unclear. Objective: The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS. Methods: Cytokine and neurofilament-light were determined in cerebrospinal fluid (CSF) of MS patients. In vitro electrophysiology and cell swelling experiments were performed to measure the effects of inflammatory cytokines in the CSF of MS patients on synaptic transmission and neuronal integrity. Results: Tumor necrosis factor-α (TNF) was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. In murine brain slices incubated in the presence of CSF from progressive MS, in fact, we observed increased spontaneous excitatory postsynaptic currents (sEPSCs) and glutamate-mediated neuronal swelling through a mechanism dependent on enhanced TNF signaling. We also suggested a pathogenic role of B cells in TNF CSF increase, exacerbation of glutamatergic transmission and neuronal damage, since CNS depletion of B cells with intrathecal rituximab caused a dramatic reduction of TNF levels, of TNF-induced sEPSC alterations, and of neurofilament CSF concentrations in a patient with progressive MS. Conclusion: Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS. |
Databáze: | OpenAIRE |
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