Novel p2x7 antagonist ameliorates the early phase of als disease and decreases inflammation and autophagy in sod1-g93a mouse model

Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Giulia Napoli, Mattia Freschi, Francesca Sironi, Paolo Pevarello, Paola Tarroni, Chiara Liberati, Caterina Bendotti, Cinzia Volonté

Research output: Contribution to journalArticlepeer-review

Abstract

Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials.

Original languageEnglish
Article number10649
JournalInternational Journal of Molecular Sciences
Volume22
Issue number19
DOIs
Publication statusPublished - Oct 1 2021

Keywords

  • ALS
  • Autophagy
  • Neuroinflammation
  • NF-B
  • NOX2
  • P2X7

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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