Wang Yuemei, Zhu Yuanbing, Wang Junmeng, Dong Longcong, Liu Shuqing, Li Sihui, Wu Qiaofeng
Acupuncture and Moxibustion College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
Front Pharmacol. 2023 Feb 7;14:1112758. doi: 10.3389/fphar.2023.1112758. eCollection 2023.
This review outlined evidence that purinergic signaling is involved in the modulation of blood-brain barrier (BBB) permeability. The functional and structural integrity of the BBB is critical for maintaining the homeostasis of the brain microenvironment. BBB integrity is maintained primarily by endothelial cells and basement membrane but also be regulated by pericytes, neurons, astrocytes, microglia and oligodendrocytes. In this review, we summarized the purinergic receptors and nucleotidases expressed on BBB cells and focused on the regulation of BBB permeability by purinergic signaling. The permeability of BBB is regulated by a series of purinergic receptors classified as P2Y, P2Y, P2Y, P2X4, P2X7, A, A, A, and A, which serve as targets for endogenous ATP, ADP, or adenosine. P2Y and P2Y antagonists could attenuate BBB damage. In contrast, P2Y-mediated chemotaxis of microglial cell processes is necessary for rapid closure of the BBB after BBB breakdown. Antagonists of P2X4 and P2X7 inhibit the activation of these receptors, reduce the release of interleukin-1 beta (IL-1β), and promote the function of BBB closure. In addition, the CD39/CD73 nucleotidase axis participates in extracellular adenosine metabolism and promotes BBB permeability through A and A on BBB cells. Furthermore, A and A receptor agonists protect BBB integrity. Thus, the regulation of the BBB by purinergic signaling is complex and affects the opening and closing of the BBB through different pathways. Appropriate selective agonists/antagonists of purinergic receptors and corresponding enzyme inhibitors could modulate the permeability of the BBB, effectively delivering therapeutic drugs/cells to the central nervous system (CNS) or limiting the entry of inflammatory immune cells into the brain and re-establishing CNS homeostasis.
本综述概述了嘌呤能信号传导参与血脑屏障（BBB）通透性调节的证据。血脑屏障的功能和结构完整性对于维持脑微环境的稳态至关重要。血脑屏障的完整性主要由内皮细胞和基底膜维持，但也受到周细胞、神经元、星形胶质细胞、小胶质细胞和少突胶质细胞的调节。在本综述中，我们总结了血脑屏障细胞上表达的嘌呤能受体和核苷酸酶，并重点关注嘌呤能信号传导对血脑屏障通透性的调节。血脑屏障的通透性由一系列分类为P2Y、P2Y、P2Y、P2X4、P2X7、A、A、A和A的嘌呤能受体调节，这些受体是内源性ATP、ADP或腺苷的作用靶点。P2Y和P2Y拮抗剂可减轻血脑屏障损伤。相反，P2Y介导的小胶质细胞过程趋化作用对于血脑屏障破坏后血脑屏障的快速闭合是必要的。P2X4和P2X7拮抗剂抑制这些受体的激活，减少白细胞介素-1β（IL-1β）的释放，并促进血脑屏障闭合功能。此外，CD39/CD73核苷酸酶轴参与细胞外腺苷代谢，并通过血脑屏障细胞上的A和A促进血脑屏障通透性。此外，A和A受体激动剂可保护血脑屏障完整性。因此，嘌呤能信号传导对血脑屏障的调节是复杂的，并通过不同途径影响血脑屏障的开放和闭合。合适的嘌呤能受体选择性激动剂/拮抗剂和相应的酶抑制剂可调节血脑屏障的通透性，有效地将治疗药物/细胞输送到中枢神经系统（CNS），或限制炎性免疫细胞进入大脑并重新建立中枢神经系统稳态。
