title: Interferon-β1a protects neurons against mitochondrial toxicity via modulation of STAT1 signaling: electrophysiological evidence.
abstract: Multiple sclerosis, one of the main causes of non-traumatic neurological disability in young adults, is an inflammatory and neurodegenerative disorder of the central nervous system. Although the pathogenesis of neuroaxonal damage occurring during the course of the disease is still largely unknown, there is accumulating evidence highlighting the potential role of mitochondria in multiple sclerosis-associated neuronal degeneration. The aim of the present study was to investigate, by utilizing electrophysiological techniques in brain striatal slices, the potential protective effects of interferon-β1a, one of the most widely used medication for multiple sclerosis, against acute neuronal dysfunction induced by mitochondrial toxins. Interferon-β1a was found to exert a dose-dependent protective effect against the progressive loss of striatal field potential amplitude induced by the mitochondrial complex I inhibitor rotenone. Interferon-β1a also reduced the generation of the rotenone-induced inward current in striatal spiny neurons. Conversely, interferon-β1a did not influence the electrophysiological effects of the mitochondrial complex II inhibitor 3-nitropropionic acid. The protective effect of interferon-β1a against mitochondrial complex I inhibition was found to be dependent on the activation of STAT1 signaling. Conversely, endogenous dopamine depletion and the modulation of the p38 MAPK and mTOR pathways did not influence the effects of interferon-β1a. During experimental autoimmune encephalomyelitis (EAE) striatal rotenone toxicity was enhanced but the protective effect of interferon-β1a was still evident. These results support future studies investigating the role played by specific intracellular signaling pathways in mediating the potential link among inflammation, mitochondrial impairment and neuroaxonal degeneration in multiple sclerosis.
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy. Electronic address: massimiliano.difilippo@unipg.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy; IRCCS Fondazione S Lucia, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy; Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Arcangeli
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Chiasserini
authors.affiliation: IRCCS Fondazione S Lucia, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.affiliation: Clinica Neurologica, Università di Perugia, Perugia, Italy; IRCCS Fondazione S Lucia, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D012402:Rotenone / Q000633:toxicity; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D018696:Neuroprotective Agents; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014475:Uncoupling Agents; D012402:Rotenone; D016899:Interferon-beta; D000068556:Interferon beta-1a
keywords: Inflammation; Interferon-β1a; Mitochondria; Multiple sclerosis; Neurodegeneration; Rotenone