Treatment with Dimethyl Fumarate Enhances Cholinergic Transmission in Multiple Sclerosis

Carolina Gabri Nicoletti, Doriana Landi, Fabrizia Monteleone, Giorgia Mataluni, Maria Albanese, Benedetta Lauretti, Camilla Rocchi, Ilaria Simonelli, Laura Boffa, Fabio Buttari, Nicola Biagio Mercuri, Diego Centonze, Girolama Alessandra Marfia

Research output: Contribution to journalArticlepeer-review


Background: Dimethyl fumarate (DMF) exerts anti-inflammatory effects in multiple sclerosis by activating the Nrf2 antioxidant pathway, which is also stimulated by acetylcholine via alpha-7 nicotinic acetylcholine receptors. In animal models, Nrf2 potentiates cholinergic synaptic plasticity. Objective: The aim of this study was to test whether treatment with DMF modulates cholinergic pathways in relapsing-remitting multiple sclerosis (RRMS). Methods: Patients starting DMF (20) or IFN-β 1a (20) and healthy subjects (20) were enrolled. Short-latency afferent inhibition (SAI), which is a transcranial stimulation measure of central cholinergic transmission, was recorded in patients and controls at baseline and, in patients only, after 6 months of treatment. Patients treated with DMF also underwent autonomic function testing to further explore peripheral and central cholinergic tone. Results: At baseline, SAI was similar in patients and in controls (p = 0.983). Treatment with DMF significantly increased SAI (p = 0.01), while IFNβ had no effect (p = 0.80). In the cold face test, DMF treatment also increased reflex bradycardia (p = 0.013), and reduced diastolic blood pressure variation (p = 0.010), further indicating its ability to stimulate cholinergic transmission. Conclusions: Treatment of MS patients with DMF results in increased cholinergic stimulation, with possible implications for neuroinflammation and neuroprotection.

Original languageEnglish
JournalCNS Drugs
Publication statusAccepted/In press - Jan 1 2019

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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