Carolina Gabri Nicoletti1, Doriana Landi1, Fabrizia Monteleone1, Giorgia Mataluni1, Maria Albanese1, Benedetta Lauretti2, Camilla Rocchi2, Ilaria Simonelli1,3, Laura Boffa1, Fabio Buttari4, Nicola Biagio Mercuri2,5, Diego Centonze6,7, Girolama Alessandra Marfia1,4. 1. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University and Hospital, Via Montpellier 1, 00133, Rome, Italy. 2. Neurology Unit, Department of Systems Medicine, Tor Vergata University and Hospital, Via Montpellier 1, 00133, Rome, Italy. 3. Service of Medical Statistics and Information Technology, Fondazione Fatebenefratelli per la Ricerca e la Formazione Sanitaria e Sociale, Lungotevere de' Cenci 5, 00186, Rome, Italy. 4. Neurology and Neurorehabilitation Units, IRCCS NEUROMED, Via Atinense 18, 86077, Pozzilli, IS, Italy. 5. Laboratory of Experimental Neurology, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143, Rome, Italy. 6. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University and Hospital, Via Montpellier 1, 00133, Rome, Italy. centonze@uniroma2.it. 7. Neurology and Neurorehabilitation Units, IRCCS NEUROMED, Via Atinense 18, 86077, Pozzilli, IS, Italy. centonze@uniroma2.it.
Abstract
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.
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 MSpatients with DMF results in increased cholinergic stimulation, with possible implications for neuroinflammation and neuroprotection.
Authors: H Tokimura; V Di Lazzaro; Y Tokimura; A Oliviero; P Profice; A Insola; P Mazzone; P Tonali; J C Rothwell Journal: J Physiol Date: 2000-03-01 Impact factor: 5.182
Authors: Chris H Polman; Stephen C Reingold; Brenda Banwell; Michel Clanet; Jeffrey A Cohen; Massimo Filippi; Kazuo Fujihara; Eva Havrdova; Michael Hutchinson; Ludwig Kappos; Fred D Lublin; Xavier Montalban; Paul O'Connor; Magnhild Sandberg-Wollheim; Alan J Thompson; Emmanuelle Waubant; Brian Weinshenker; Jerry S Wolinsky Journal: Ann Neurol Date: 2011-02 Impact factor: 10.422