Department of Global Healthcare, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Cells. 2021 Feb 18;10(2):434. doi: 10.3390/cells10020434.
P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential.
P2X7 受体（P2X7Rs）属于 ATP 门控非选择性阳离子通道家族。小胶质细胞是表达 P2X7Rs 的主要细胞类型之一。小胶质细胞 P2X7Rs 的激活会导致促炎细胞因子（如白细胞介素-1β，IL-1β）的释放。这种反应与中枢神经系统中的神经炎症状态以及各种疾病有关，包括神经性疼痛。因此，P2X7R 可能代表一个潜在的治疗靶点。在本研究中，我们通过高通量筛选对临床批准药物的化学文库（1979 种化合物）进行了筛选，结果表明钙通道阻滞剂西尼地平对啮齿动物和人类 P2X7R 具有抑制作用。在原代培养的大鼠小胶质细胞中，西尼地平抑制了 P2X7R 介导的 Ca 反应和 IL-1β 的释放。此外，在神经病理性疼痛大鼠模型中，鞘内给予西尼地平可逆转神经损伤引起的机械性痛觉过敏，这是神经病理性疼痛的主要症状。这些结果表明西尼地平对小胶质细胞 P2X7R 介导的炎症反应和神经病理性疼痛具有新的抑制作用，提示其具有治疗潜力。
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