Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis

Objective: Fingolimod is an effective disease modifying therapy for multiple sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5. mg/day. Methods: Paired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60. days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5. ms) and intracortical facilitation (at 7, 9, 11 and 13. ms) were estimated at T0 and T1. Results: Intracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition. Conclusions: Fingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate. Significance: This is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitotoxicity in vivo, as already seen in animal models.