P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis
P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis
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DOI：
10.3389/fnmol.2020.00093
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发表时间：
2020-06
影响因子：
4.8
通讯作者：
C. Ruiz-Ruiz-C.-Ruiz-Ruiz-1390148218;Francesco Calzaferri;Antonio G. García
中科院分区：
文献类型：
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作者：
C. Ruiz-Ruiz-C.-Ruiz-Ruiz-1390148218;Francesco Calzaferri;Antonio G. García
本文综述了嘌呤能离子型受体P2 X7（P2 X7 R）作为开发延缓肌萎缩侧索硬化（ALS）患者发病和/或疾病进展药物的潜在靶点。在描述临床和遗传ALS特征之后，分析了基于一系列蛋白质突变的转基因小鼠疾病模型的优点和缺点，特别是Cu/Zn超氧化物歧化酶（SOD 1）、TAR-DNA结合蛋白-43（TDP-43）、融合于肉瘤/易位于肉瘤（FUS）和9号染色体开放阅读框72（C9 orf 72）。虽然价值有限，但这些模型对于在进入临床试验之前研究新化合物的概念证明至关重要。作者还提供了ALS发病机制的描述，包括蛋白质聚集、钙依赖性兴奋性毒性、钙结合蛋白功能障碍、超微结构线粒体改变、线粒体钙处理中断和活性氧（ROS）过度产生。了解疾病的致病途径可能有助于识别新的药物靶点。随后，神经炎症与P2 X7 Rs在ALS发病机制的描述，以了解放置使用P2 X7 R拮抗剂作为一种新的治疗ALS的药理学方法的基本原理。这是假设P2 X7 R阻断剂可以减轻神经炎症状态，间接导致ALS患者的神经保护和更高的运动神经元存活的基础。
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.