P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis

Abstract

This review focuses on the purinergic ionotropic receptor P2X7 (P2X7R) as a potential target for developing drugs that delay the onset and/or disease progression in patients with amyotrophic lateral sclerosis (ALS). Description of clinical and genetic ALS features is followed by an analysis of advantages and drawbacks of transgenic mouse models of disease based on mutations in a bunch of proteins, particularly Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein-43 (TDP-43), Fused in Sarcoma/Translocated in Sarcoma (FUS), and Chromosome 9 open reading frame 72 (C9orf72). Though of limited value, these models are however critical to study the proof of concept of new compounds, before reaching clinical trials. The authors also provide a description of ALS pathogenesis including protein aggregation, calcium-dependent excitotoxicity, dysfunction of calcium-binding proteins, ultrastructural mitochondrial alterations, disruption of mitochondrial calcium handling, and overproduction of reactive oxygen species (ROS). Understanding disease pathogenic pathways may ease the identification of new drug targets. Subsequently, neuroinflammation linked with P2X7Rs in ALS pathogenesis is described in order to understand the rationale of placing the use of P2X7R antagonists as a new therapeutic pharmacological approach to ALS. This is the basis for the hypothesis that a P2X7R blocker could mitigate the neuroinflammatory state, indirectly leading to neuroprotection and higher motoneuron survival in ALS patients.

Duality of P2X7 Receptor in Amyotrophic Lateral Sclerosis

“…The studies about the involvement of purinergic signaling in neurodegenerative and neuroinflammatory conditions are certainly convincing (Volontéet al, 2003;Franke and Illes, 2006;Burnstock, 2008;Khakh and North, 2012;Sperlaǵh and Illes, 2014;Tewari and Seth, 2015;Burnstock, 2016;Burnstock, 2017a;Burnstock, 2017b) and now flourishing also on ALS and P2X7, in particular (Volontéet al, 2011;Volontéet al, 2012;Volontéet al, 2016;Sebastião et al, 2018;Ciesĺak et al, 2019;Ruiz-Ruiz et al, 2020). Moreover, because of the evolution of always more specific and potent P2X7 antagonists with a focus on CNS indications (Rech et al, 2016;Pevarello et al, 2017), we can optimistically expect that in the near future some new generation P2X7 drugs might be listed on the formulary and medication plan for ALS patients.…”

Increased cerebrospinal fluid adenosine 5'-triphosphate in patients with amyotrophic lateral sclerosis

“…Due to these variation, CSF ATP levels may be less useful as a prognostic marker in patients with ALS. Conversely, in light of their potential as a therapeutic target of ATP receptor antagonists for patients with ALS [ 37 ], it is assumed that CSF ATP levels are useful biomarkers for evaluating the effect of such a new therapy, as would be the case for serum uric acid in the future.…”

P2X7 Receptors in Neurodegeneration: Potential Therapeutic Applications From Basic to Clinical Approaches

“…JNJ-47965567 significantly reduced temporal lobe epilepsy characterized by a pattern of selective neuronal loss and reactive gliosis (Jimenez-Pacheco et al, 2016 ). Chronic administration of JNJ-47965567 (4X/week) to SOD mice model of ALS modified disease progression in female animals, but had no effect in male animals, suggesting partial effect of P2X 7 R in progression of ALS (Ruiz-Ruiz et al, 2020 ).…”

“…Increased expression of P2X 7 Rs has been detected in microglia (D'ambrosi et al, 2009 ; Rudnick et al, 2017 ) or astrocytes (Gandelman et al, 2010 ; Apolloni et al, 2014 ) isolated from superoxide dismutase 1 (SOD1 G93A ) mouse model of ALS, and application of the P2X 7 R antagonist BBG improved spinal cord pathology and ameliorated the disease in these mice (Apolloni et al, 2014 ; Bartlett et al, 2017 ). Additionally, more potent and selective P2X 7 R antagonists such as A804598 and JNJ-47965567 have provided some beneficial effects in ALS mouse models (Fabbrizio et al, 2017 ; Ly et al, 2020 ; Ruiz-Ruiz et al, 2020 ). Furthermore, ATP-induced activation of P2X 7 R has shown to activate kinase ERK1/2 and NOX2 in microglia of SOD1 G93A mice (Apolloni et al, 2013 ).…”