title: In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity.
abstract: In multiple sclerosis (MS), a candidate downstream mechanism for neuronal injury is glutamate (Glu)-induced excitotoxicity, leading to toxic increases in intraneuronal Ca(2+) . Here, we used in vivo two-photon imaging in the brain of TN-XXL transgenic Ca(2+) reporter mice to test whether promising oral MS therapeutics, namely fingolimod, dimethyl fumarate, and their respective metabolites fingolimod-phosphate and monomethyl fumarate, can protect neurons against acute glutamatergic excitotoxic damage. We also assessed whether these drugs can protect against excitotoxicity in vitro using primary cortical neurons, and whether they can directly inhibit Glu release from pathogenic T-helper 17 lymphocytes. In vivo, direct and acute (1 h) administration of 100 mM Glu to the brainstem resulted in a rapid and significant up-regulation in neuronal Ca(2+) signaling as well as morphological excitotoxic changes that were attenuated by the NMDA-receptor antagonist MK801. Direct CNS administration of MS drugs prior to Glu significantly delayed or reduced, but did not prevent the neuronal Ca(2+) increase or morphological changes. In vitro, prolonged (24 h) treatment of primary neurons with the fumarates significantly protected against neurotoxicity induced by Glu as well as NMDA, similar to MK801. Furthermore, monomethyl fumerate significantly reduced Glu release from pathogenic T-helper 17 lymphocytes. Overall, these data suggest that MS drugs may mediate neuroprotection via excitotoxicity modulating effects. Evidence suggests MS pathogenesis may involve neuronal excitotoxicity, induced by local release of glutamate. However, current MS drugs, including dimethyl fumerate (DMF) and fingolimod (FTY720) are largely anti-inflammatory and not yet fully tested for their neuroprotective potential. Here, we show that the drugs, in particular DMF metabolite monomethyl fumerate (MMF), protect neurons by excitotoxicity modulating effects. Th17, T-helper 17.
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Luchtman
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Gollan
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Ellwardt
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Birkenstock
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Robohm
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Siffrin
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism*; D056747:Immunomodulation / Q000276:immunology*; D007608:Kainic Acid / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D018696:Neuroprotective Agents; D018698:Glutamic Acid; D007608:Kainic Acid
keywords: calcium; excitotoxicity; glutamate; multiple sclerosis; neuroprotection; two-photon imaging