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.

这项审查集中在嘌呤能离子受体P2X7（P2X7R）作为开发药物的潜在目标，该药物可延迟肌萎缩性侧索硬化症（ALS）患者的发作和/或疾病进展。在描述临床和遗传ALS特征之后，基于一堆蛋白质（尤其是Cu / Zn超氧化物歧化酶（SOD1），TAR-DNA结合蛋白43（TDP））中的突变，分析了转基因小鼠疾病模型的优缺点-43），在肉瘤中融合/在肉瘤中转移（FUS）和9号染色体开放阅读框72（C9orf72）。尽管价值有限，但是这些模型对于在进行临床试验之前研究新化合物概念的证明至关重要。作者还提供了ALS发病机理的描述，包括蛋白质聚集，钙依赖的兴奋性毒性，钙结合蛋白功能异常，线粒体超微结构改变，线粒体钙处理中断以及活性氧（ROS）过量产生。了解疾病的致病途径可以简化新药靶标的鉴定。随后，描述了与ALS发病机理中的P2X7Rs相关的神经炎症，以了解将P2X7R拮抗剂用作ALS的新治疗药理学方法的原理。这是P2X7R阻滞剂可以减轻神经炎症状态，间接导致ALS患者神经保护和更高的运动神经元存活的假说的基础。了解疾病的致病途径可以简化新药靶标的鉴定。随后，描述了与ALS发病机理中的P2X7Rs相关的神经炎症，以了解将P2X7R拮抗剂用作ALS的新治疗药理学方法的原理。这是P2X7R阻滞剂可以减轻神经炎症状态，间接导致ALS患者神经保护和更高的运动神经元存活的假说的基础。了解疾病的致病途径可以简化新药靶标的鉴定。随后，描述了与ALS发病机理中的P2X7Rs相关的神经炎症，以了解将P2X7R拮抗剂用作ALS的新治疗药理学方法的原理。这是P2X7R阻滞剂可以减轻神经炎症状态，间接导致ALS患者神经保护和更高的运动神经元存活的假说的基础。