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Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial

Andrea Mancini1, Michela Tantucci1, Petra Mazzocchetti1

  • 1Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.

Neurobiology of Disease
|January 13, 2018
PubMed

Insights

Inflammation in multiple sclerosis (MS) increases neuronal vulnerability to mitochondrial dysfunction. Inhibiting microglia and the nitric oxide (NO) pathway protects neurons, suggesting new therapeutic targets for MS neurodegeneration.

Area of Science:

  • Neuroscience
  • Immunology
  • Mitochondrial Biology

Background:

  • Multiple sclerosis (MS) involves inflammation and neuro-axonal degeneration.
  • Immune mechanisms are hypothesized to drive MS neurodegeneration.
  • Mitochondrial dysfunction and energy deficits are implicated in MS pathogenesis.

Purpose of the Study:

  • To investigate if inflammation in experimental autoimmune encephalomyelitis (EAE) enhances neuronal vulnerability to mitochondrial complex IV inhibition.
  • To identify potential cellular and molecular targets for mitigating this vulnerability.

Main Methods:

  • Used striatal electrophysiological field-potential recordings in a rodent model of MS (EAE).
  • Assessed neuronal response to blockade of mitochondrial complex IV.
  • Evaluated the effects of pharmacological inhibition of microglia and the nitric oxide (NO) pathway (sGC/PKG).

Main Results:

  • Neuronal susceptibility to mitochondrial complex IV inhibition was significantly increased during the acute relapsing phase of EAE.
  • Pharmacological inhibition of microglia and the NO pathway (sGC/PKG) counteracted this enhanced neuronal vulnerability.
  • Mitochondrial complex IV plays a critical role in neuronal energy homeostasis during EAE.

Conclusions:

  • Pathological processes in experimental MS, including microglia activation and the NO pathway, increase neuronal susceptibility to mitochondrial complex IV inhibition.
  • Microglia and the NO pathway represent promising pharmacological targets for preserving neuronal function in MS.
  • Targeting mitochondrial complex IV may be a strategy to maintain neuronal energetic homeostasis in MS.
Keywords:
MicrogliaMitochondrial dysfunctionMultiple sclerosisNeurodegenerationNeuroprotective strategiesNitric oxide

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