CNS Drugs

, Volume 33, Issue 11, pp 1133–1139 | Cite as

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 CentonzeEmail author
  • Girolama Alessandra Marfia
Original Research Article



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.


The aim of this study was to test whether treatment with DMF modulates cholinergic pathways in relapsing-remitting multiple sclerosis (RRMS).


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.


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.


Treatment of MS patients with DMF results in increased cholinergic stimulation, with possible implications for neuroinflammation and neuroprotection.


Compliance with Ethical Standards

Conflict of interest

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, and Girolama Alessandra Marfia declare that they have no conflict of interest.

Ethical approval

The study was approved by the local Ethics Committee of the University Hospital Tor Vergata, Rome (Italy).

Informed consent

All participants signed a written informed consent.


This study did not receive any financial support.


  1. 1.
    Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–97.CrossRefGoogle Scholar
  2. 2.
    Phillips J, Fox R. BG-12 in multiple sclerosis. Semin Neurol. 2013;33:56–65.CrossRefGoogle Scholar
  3. 3.
    Li W, Kong A-N. Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog. 2009;48:91–104.CrossRefGoogle Scholar
  4. 4.
    Parada E, Egea J, Buendia I, et al. The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxid Redox Signal. 2013;19:1135–48.CrossRefGoogle Scholar
  5. 5.
    Staab TA, Griffen TC, Corcoran C, et al. The conserved SKN-1/Nrf2 stress response pathway regulates synaptic Function in Caenorhabditis elegans. PLoS Genet. 2013;9:e1003354.CrossRefGoogle Scholar
  6. 6.
    Di Bari M, Di Pinto G, Reale M, et al. Cholinergic system and neuroinflammation: implication in multiple sclerosis. Cent Nerv Syst Agents Med Chem. 2017;17:109–15.PubMedGoogle Scholar
  7. 7.
    Foucault-Fruchard L, Antier D. Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases. Neural Regen Res. 2017;12:1418.CrossRefGoogle Scholar
  8. 8.
    Di Lazzaro V, Oliviero A, Profice P, et al. Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex. Exp Brain Res. 2000;135:455–61.CrossRefGoogle Scholar
  9. 9.
    Tokimura H, Di Lazzaro V, Tokimura Y, et al. Short latency inhibition of human hand motor cortex by somatosensory input from the hand. J Physiol. 2000;523:503–13.CrossRefGoogle Scholar
  10. 10.
    Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.CrossRefGoogle Scholar
  11. 11.
    Rossi S, Rocchi C, Studer V, et al. The autonomic balance predicts cardiac responses after the first dose of fingolimod. Mult Scler. 2015;21:206–16.CrossRefGoogle Scholar
  12. 12.
    Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302.CrossRefGoogle Scholar
  13. 13.
    Rossi S, Hallett M, Rossini PM, et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009;120:2008–39.CrossRefGoogle Scholar
  14. 14.
    Di Lazzaro V, Pilato F, Dileone M, et al. Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition: dissociated effects of benzodiazepines on SAI. J Physiol. 2005;569:315–23.CrossRefGoogle Scholar
  15. 15.
    Di Lazzaro V, Pilato F, Dileone M, et al. In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias. Neurology. 2006;66:1111–3.CrossRefGoogle Scholar
  16. 16.
    Mathias CJ. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. 5th ed. Oxford: Oxford University Press; 2013.CrossRefGoogle Scholar
  17. 17.
    Turco CV, El-Sayes J, Savoie MJ, et al. Short- and long-latency afferent inhibition; uses, mechanisms and influencing factors. Brain Stimul. 2018;11:59–74.CrossRefGoogle Scholar
  18. 18.
    Di Lazzaro V, Oliviero A, Tonali PA, et al. Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology. 2002;59:392–7.CrossRefGoogle Scholar
  19. 19.
    Di Lazzaro V, Pilato F, Dileone M, et al. Functional evaluation of cerebral cortex in dementia with Lewy bodies. Neuroimage. 2007;37:422–9.CrossRefGoogle Scholar
  20. 20.
    Nardone R, Bergmann J, Christova M, et al. Short latency afferent inhibition differs among the subtypes of mild cognitive impairment. J Neural Transm. 2012;119:463–71.CrossRefGoogle Scholar
  21. 21.
    Celebi O, Temuçin ÇM, Elibol B, et al. Short latency afferent inhibition in Parkinson’s disease patients with dementia. Mov Disord. 2012;27:1052–5.CrossRefGoogle Scholar
  22. 22.
    Jiang W, St-Pierre S, Roy P, et al. Infiltration of CCR22+ Ly6Chigh proinflammatory monocytes and neutrophils into the central nervous system is modulated by nicotinic acetylcholine receptors in a model of multiple sclerosis. J Immunol. 2016;196:2095–108.CrossRefGoogle Scholar
  23. 23.
    Nizri E, Irony-Tur-Sinai M, Faranesh N, et al. Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine. J Neuroimmunol. 2008;203:12–22.CrossRefGoogle Scholar
  24. 24.
    Fields RD, Dutta DJ, Belgrad J, et al. Cholinergic signaling in myelination: cholinergic signaling in myelination. Glia. 2017;65:687–98.CrossRefGoogle Scholar
  25. 25.
    Kooi E-J, Prins M, Bajic N, et al. Cholinergic imbalance in the multiple sclerosis hippocampus. Acta Neuropathol. 2011;122:313–22.CrossRefGoogle Scholar
  26. 26.
    Khurana RK, Watabiki S, Hebel JR, et al. Cold face test in the assessment of trigeminal-brainstem-vagal function in humans. Ann Neurol. 1980;7:144–9.CrossRefGoogle Scholar
  27. 27.
    Majkutewicz I, Kurowska E, Podlacha M, et al. Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats. Behav Brain Res. 2016;308:24–37.CrossRefGoogle Scholar
  28. 28.
    Li R, Rezk A, Ghadiri M, et al. Dimethyl fumarate treatment mediates an anti-inflammatory shift in B cell subsets of patients with multiple sclerosis. J Immunol. 2017;198:691–8.CrossRefGoogle Scholar
  29. 29.
    Wilms H, Sievers J, Rickert U, et al. Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation. J Neuroinflamm. 2010;7:30.CrossRefGoogle Scholar
  30. 30.
    Parodi B, Rossi S, Morando S, et al. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta Neuropathol. 2015;130:279–95.CrossRefGoogle Scholar
  31. 31.
    Brawek B, Garaschuk O. Microglial calcium signaling in the adult, aged and diseased brain. Cell Calcium. 2013;53:159–69.CrossRefGoogle Scholar
  32. 32.
    Blad CC, Ahmed K, IJzerman AP, et al. Biological and pharmacological roles of HCA receptors. Adv Pharmacol. 2011;62:219–50.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Carolina Gabri Nicoletti
    • 1
  • Doriana Landi
    • 1
  • Fabrizia Monteleone
    • 1
  • Giorgia Mataluni
    • 1
  • Maria Albanese
    • 1
  • Benedetta Lauretti
    • 2
  • Camilla Rocchi
    • 2
  • Ilaria Simonelli
    • 1
    • 4
  • Laura Boffa
    • 1
  • Fabio Buttari
    • 3
  • Nicola Biagio Mercuri
    • 2
    • 5
  • Diego Centonze
    • 1
    • 3
    Email author
  • Girolama Alessandra Marfia
    • 1
    • 3
  1. 1.Multiple Sclerosis Clinical and Research Unit, Department of Systems MedicineTor Vergata University and HospitalRomeItaly
  2. 2.Neurology Unit, Department of Systems MedicineTor Vergata University and HospitalRomeItaly
  3. 3.Neurology and Neurorehabilitation UnitsIRCCS NEUROMEDPozzilliItaly
  4. 4.Service of Medical Statistics and Information TechnologyFondazione Fatebenefratelli per la Ricerca e la Formazione Sanitaria e SocialeRomeItaly
  5. 5.Laboratory of Experimental NeurologyIRCCS Fondazione Santa LuciaRomeItaly

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