Territo Paul R, Zarrinmayeh Hamideh
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Cell Neurosci. 2021 Apr 6;15:617036. doi: 10.3389/fncel.2021.617036. eCollection 2021.
Purinergic receptors play important roles in central nervous system (CNS), where the bulk of these receptors are implicated in neuroinflammatory responses and regulation of cellular function of neurons, microglial and astrocytes. Within the P2X receptor family, P2X receptor is generally known for its inactivity in normal conditions and activation by moderately high concentrations (>100 μM) of extracellular adenosine 5'-triphosphate (ATP) released from injured cells as a result of brain injury or pathological conditions. Activation of P2XR contributes to the activation and proliferation of microglia and directly contribute to neurodegeneration by provoking microglia-mediated neuronal death, glutamate-mediated excitotoxicity, and NLRP3 inflammasome activation that results in initiation, maturity and release of the pro-inflammatory cytokines and generation of reactive oxygen and nitrogen species. These components of the inflammatory response play important roles in many neural pathologies and neurodegeneration disorders. In CNS, expression of P2XR on microglia, astrocytes, and oligodendrocytes are upregulated under neuroinflammatory conditions. Several studies have demonstrated beneficial effects of the P2X receptor antagonists in animal model systems of neurodegenerative diseases. A number of specific and selective P2X receptor antagonists have been developed, but only few of them have shown efficient brain permeability. Finding potent and selective P2X receptor inhibitors which are also CNS penetrable and display acceptable pharmacokinetics (PK) has presented challenges for both academic researchers and pharmaceutical companies. In this review, we discuss the role of P2X receptor function in neurodegenerative diseases, the pharmacological inhibition of the receptor, and PET radiopharmaceuticals which permit non-invasive monitoring of the P2X receptor contribution to neuroinflammation associated with neurodegeneration.
嘌呤能受体在中枢神经系统（CNS）中发挥重要作用，其中大部分受体与神经炎症反应以及神经元、小胶质细胞和星形胶质细胞的细胞功能调节有关。在P2X受体家族中，P2X受体通常在正常条件下无活性，而在脑损伤或病理状况导致损伤细胞释放中等高浓度（>100μM）的细胞外5'-三磷酸腺苷（ATP）时被激活。P2XR的激活有助于小胶质细胞的活化和增殖，并通过引发小胶质细胞介导的神经元死亡、谷氨酸介导的兴奋性毒性以及NLRP3炎性小体激活，直接导致神经退行性变，NLRP3炎性小体激活会引发促炎细胞因子的产生、成熟和释放，以及活性氧和氮物种的生成。炎症反应的这些成分在许多神经病理学和神经退行性疾病中起重要作用。在中枢神经系统中，神经炎症条件下小胶质细胞、星形胶质细胞和少突胶质细胞上P2XR的表达会上调。多项研究已证明P2X受体拮抗剂在神经退行性疾病动物模型系统中的有益作用。已经开发出许多特异性和选择性P2X受体拮抗剂，但其中只有少数显示出有效的脑渗透性。寻找强效且选择性的P2X受体抑制剂，使其既能穿透中枢神经系统又具有可接受的药代动力学（PK），这对学术研究人员和制药公司来说都是挑战。在这篇综述中，我们讨论了P2X受体功能在神经退行性疾病中的作用、该受体的药理学抑制作用，以及允许对P2X受体在与神经退行性变相关的神经炎症中的作用进行无创监测的PET放射性药物。
