Treatment with Dimethyl Fumarate Enhances Cholinergic Transmission in Multiple Sclerosis

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.