title: Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate.
abstract: Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection.
authors.affiliation: Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: de Ceglia
authors.affiliation: Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy; Department of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele University, Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Chaabane
authors.affiliation: Neuroengineering and Medical Robotics Laboratory, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy; Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Biffi
authors.affiliation: Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bergamaschi
authors.affiliation: Neuroengineering and Medical Robotics Laboratory, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Ferrigno
authors.affiliation: Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Amadio
authors.affiliation: Neurophysiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.affiliation: Advanced Light and Electron Microscopy Bio-Imaging Centre, Experimental Imaging Centre, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Mazzocchi
authors.affiliation: Department of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele University, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Taverna
authors.affiliation: Center for Neuroscience and Dept. of Theoretical and Applied Sciences, Biomedical Division, University of Insubria, 21052 Busto Arsizio, Italy.
authors.forename: Lia
authors.initials: L
authors.lastname: Forti
authors.affiliation: Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy. Electronic address: martino.gianvito@hsr.it.
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.affiliation: Advanced Light and Electron Microscopy Bio-Imaging Centre, Experimental Imaging Centre, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Menegon
authors.affiliation: Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy. Electronic address: Muzio.luca@hsr.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology*; D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D055366:Synaptic Potentials / Q000187:drug effects
chemical_list: D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; C003915:diminazene aceturate; D004133:Diminazene
keywords: ASICs; Diminazene Aceturate; MEA; MRI spectroscopy; Multiple sclerosis