Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis

Paolo Calabresi, Andrea Mancini, Michela Tantucci, Petra Mazzocchetti, Antonio De Iure, Valentina Durante, Lara Macchioni, Lorenzo Gaetani, Cinzia Costa, Alessandro Tozzi, Massimiliano Di Filippo

Risultato della ricerca: Contributo in rivistaArticolo in rivista

11 Citazioni (Scopus)

Abstract

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets.
Lingua originaleEnglish
pagine (da-a)97-108
Numero di pagine12
RivistaNeurobiology of Disease
Volume113
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Animals
  • Cyclic GMP
  • Cyclic GMP-Dependent Protein Kinases
  • Encephalomyelitis, Autoimmune, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia
  • Mitochondria
  • Mitochondrial dysfunction
  • Multiple Sclerosis
  • Multiple sclerosis
  • Neurodegeneration
  • Neurons
  • Neuroprotective strategies
  • Nitric Oxide
  • Nitric oxide
  • Organ Culture Techniques
  • Signal Transduction
  • Sodium Azide

Fingerprint Entra nei temi di ricerca di 'Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis'. Insieme formano una fingerprint unica.

Cita questo