title: Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration.
abstract: 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.
  
  
  CONCLUSIONS
  Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bergami
authors.forename: Giulia
authors.initials: G
authors.lastname: Sancesario
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.forename: Gottardo
authors.initials: G
authors.lastname: De Angelis
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000378:metabolism*; D009410:Nerve Degeneration / Q000134:cerebrospinal fluid / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid*; D055815:Young Adult
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: B cells; TNF-α; cerebrospinal fluid; glutamate; inflammation; synaptic transmission