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.
Highlights
In amyotrophic lateral sclerosis (ALS), one of the most aggressive neurodegenerative diseases of adulthood, neuroinflammation is recognized as the pathological mechanism contributing to motor neuron death [1,2,3]
As it was expected by the pharmacokinetic studies, the selective and blood brain barrier permeable P2X7 antagonist, AXX71, administered daily and intraperitoneally at 30 mg/kg for two weeks reached the CNS districts, as shown by the mean concentration of the compound in the blood, brain and spinal cord of SOD1-G93A mice that resulted in 1295 ng/mL, 1102 ng/g, and 638 ng/g, respectively (Table 2)
We studied the effect of the AXX71-dependent antagonism of P2X7 on SOD1 expression and aggregation, and autophagy, by measuring the levels of SOD1, LC3B-II, and SQSTM1/p62 proteins
Summary
In amyotrophic lateral sclerosis (ALS), one of the most aggressive neurodegenerative diseases of adulthood, neuroinflammation is recognized as the pathological mechanism contributing to motor neuron death [1,2,3]. We have established that A804598 positively modulates autophagy in vitro and in vivo in SOD1G93A models [31]. This is not surprising, because P2X7 plays a direct critical role in the regulation of the autophagic flux, and in the maturation and autophagy-based secretion of IL-1β from microglial cells [33]. Impaired autophagy is a mechanism of injury and death in motor neurons [35], contributing to ALS disease progression. We have tested new-generation P2X7 antagonists, the Axxam proprietary compound AXX71 and AXX13, with high selectivity, affinity, and blood brain barrier permeability, for their efficacy on inflammatory/autophagy mechanisms and motor skills in the SOD1-G93A mouse model of ALS
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