Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate

Roberta de Ceglia, Linda Chaabane, Emilia Biffi, Andrea Bergamaschi, Giancarlo Ferrigno, Stefano Amadio, Ubaldo Del Carro, Nausicaa Mazzocchi, Giancarlo Comi, Veronica Bianchi, Stefano Taverna, Lia Forti, Patrizia D'Adamo, Gianvito Martino, Andrea Menegon, Luca Muzio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)263-276
Number of pages14
JournalBrain, Behavior, and Immunity
Volume45
DOIs
Publication statusPublished - Mar 1 2015

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Keywords

  • ASICs
  • Diminazene Aceturate
  • MEA
  • MRI spectroscopy
  • Multiple sclerosis

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems
  • Medicine(all)

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