Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model.
Savina ApolloniPaola FabbrizioSusanna AmadioGiulia NapoliMattia FreschiFrancesca SironiPaolo PevarelloPaola TarroniChiara LiberatiCaterina BendottiCinzia VolontéPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- amyotrophic lateral sclerosis
- mouse model
- oxidative stress
- clinical trial
- signaling pathway
- cell death
- inflammatory response
- endoplasmic reticulum stress
- traumatic brain injury
- stem cells
- adipose tissue
- lipopolysaccharide induced
- single molecule
- skeletal muscle
- cerebral ischemia
- bone marrow
- spinal cord injury
- blood brain barrier
- high resolution
- metabolic syndrome