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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with upper and lower motor neuron (MN) loss in the cerebral cortex, brainstem, and spinal cord
In light of the scarce therapeutic tools currently available to delay the appearance of symptoms or disease progression, we will analyze here the following aspects of ALS to be able to extract meaningful conclusions for new drug therapy approaches: (i) genetic features; (ii) mouse models of ALS, based on gene mutations found in patients; (iii) pathogenic signaling pathways involved in MN death, and potential drug targets; (iv) neuroinflammation and the role of the purinergic P2X7 receptor (P2X7R) in disease pathogenesis; (v) available ligands for P2X7Rs; (vi) proof of concept of efficacy of some P2X7R antagonists in mouse models of ALS; (vii) past and ongoing clinical trial (CT); and (viii) conclusions and perspectives
An add-on riluzole therapy phase III CT reported significant outcomes in ALS patients treated with masitinib [Masitinib in Combination With Riluzole for the Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS), 2018]
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with upper and lower motor neuron (MN) loss in the cerebral cortex, brainstem, and spinal cord. Clinical symptoms start at 55 ± 15 years, with gradual loss of daily motor activities, ambulation, speech and swallowing impairment, compromised respiration, progressive paralysis, and death within 3–5 years after diagnosis. Due to this prompt death, disease prevalence is low; in the UK, the incidence is 1 in 472 women and 1 in 350 men (Alonso et al, 2009), while in the USA, there are about 16,000 affected patients and 5,000 new diagnosed cases every year (The ALS association, 2020). In light of the scarce therapeutic tools currently available to delay the appearance of symptoms or disease progression, we will analyze here the following aspects of ALS to be able to extract meaningful conclusions for new drug therapy approaches: (i) genetic features; (ii) mouse models of ALS, based on gene mutations found in patients; (iii) pathogenic signaling pathways involved in MN death, and potential drug targets; (iv) neuroinflammation and the role of the purinergic P2X7 receptor (P2X7R) in disease pathogenesis; (v) available ligands for P2X7Rs; (vi) proof of concept of efficacy of some P2X7R antagonists in mouse models of ALS; (vii) past and ongoing CTs; and (viii) conclusions and perspectives
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