Treatment with Dimethyl Fumarate Enhances Cholinergic Transmission in Multiple Sclerosis

• Published in: CNS drugs Vol. 33; no. 11; pp. 1133 - 1139
• Main Authors: Nicoletti, Carolina Gabri, Landi, Doriana, Monteleone, Fabrizia, Mataluni, Giorgia, Albanese, Maria, Lauretti, Benedetta, Rocchi, Camilla, Simonelli, Ilaria, Boffa, Laura, Buttari, Fabio, Mercuri, Nicola Biagio, Centonze, Diego, Marfia, Girolama Alessandra
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2019; Springer Nature B.V
• Subjects: Acetylcholine receptors (nicotinic); Animal models; Antioxidants; Autonomic nervous system; Blood pressure; Bradycardia; Cholinergic transmission; Clinical medicine; Inflammation; Latency; Medicine; Medicine & Public Health; Multiple sclerosis; Neurology; Neuroprotection; Neurosciences; Original Research Article; Pharmacotherapy; Psychiatry; Psychopharmacology; Sensory neurons; Synaptic plasticity; Transcranial magnetic stimulation; β-Interferon
• ISSN: 1172-7047; 1179-1934; 1179-1934
• DOI: 10.1007/s40263-019-00676-6

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.