Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis

Savina Apolloni, Susanna Amadio, Chiara Parisi, Alessandra Matteucci, Rosa L. Potenza, Monica Armida, Patrizia Popoli, Nadia D'Ambrosi, Cinzia Volonté

Research output: Contribution to journalArticle

Abstract

In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a 'gene modifier' in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemiareperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1β, interleukin-10 and brain-derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.

Original languageEnglish
Pages (from-to)1101-1109
Number of pages9
JournalDMM Disease Models and Mechanisms
Volume7
Issue number9
DOIs
Publication statusPublished - Sep 1 2014

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Amyotrophic Lateral Sclerosis
Pathology
Spinal Cord
Microglia
Purinergic P2X7 Receptors
Modifier Genes
Neuropsychiatry
NADPH Oxidase
Brain-Derived Neurotrophic Factor
Neurology
Asymptomatic Diseases
Interleukin-1
Interleukin-10
Neurons
Neuralgia
Motor Neurons
Toxicity
Rats
Brain
Blood-Brain Barrier

Keywords

  • ALS
  • Brilliant Blue G
  • Microglia
  • Motor neuron
  • P2X7

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)
  • Medicine(all)

Cite this

Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. / Apolloni, Savina; Amadio, Susanna; Parisi, Chiara; Matteucci, Alessandra; Potenza, Rosa L.; Armida, Monica; Popoli, Patrizia; D'Ambrosi, Nadia; Volonté, Cinzia.

In: DMM Disease Models and Mechanisms, Vol. 7, No. 9, 01.09.2014, p. 1101-1109.

Research output: Contribution to journalArticle

Apolloni, Savina ; Amadio, Susanna ; Parisi, Chiara ; Matteucci, Alessandra ; Potenza, Rosa L. ; Armida, Monica ; Popoli, Patrizia ; D'Ambrosi, Nadia ; Volonté, Cinzia. / Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. In: DMM Disease Models and Mechanisms. 2014 ; Vol. 7, No. 9. pp. 1101-1109.
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