OBJECTIVE: The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons.
METHODS:We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-α, of interleukin-1β (IL-1β), and of IL-1 receptor antagonist (IL-1ra, an IL-1 blocker), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS).
RESULTS: CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in cell culture through a mechanism dependent on enhanced IL-1β signaling and increased glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor stimulation. Furthermore, IL-1β/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, a measure of glutamate transmission. Finally, we identified transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1β on central glutamatergic synapses.
INTERPRETATION: Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS.
Glutamate is the major neurotransmitter (chemical that triggers nerve impulses) that stimulates nerves. However if a nerve gets too much stimulation it can trigger the cells to commit suicide which is known as excitotoxicity. Using mouse brain tissue the electrical activity of nerves was measured before and after cerebrospinal fluid was used to bathe the brain tissue. This was taken when MS was active and when it was non-active. It was found that when disease was active there were chemicals released that could cause nerve damage. Using this approach one of the damaging molecules was identified and away that it can stimulation of glutamate through AMPA glutamate receptors. Glutamate receptor anagonists could be a potential treatment that could be suggested from this work, but have the potential to cause side-effects or Vannilod receptor antagonists could be an alternative new avenue for treatment.