Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms221910649
Keywords
ALS; autophagy; neuroinflammation; NF-kappa B; NOX2; P2X7
Funding
- AriSLA grant PATH-for-ALS
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Amyotrophic lateral sclerosis (ALS) is a neuroinflammatory disease where the role of P2X7 receptor has been highlighted, and the novel P2X7 antagonist AXX71 shows potential therapeutic value in ALS by targeting microglia-related proinflammatory markers and autophagy during the early symptomatic phase of the disease. This suggests that P2X7 modulation could be further explored as a therapeutic strategy in preclinical studies and applied in ALS clinical trials.
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.
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