College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China.
College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China.
Exp Neurol. 2024 Sep;379:114852. doi: 10.1016/j.expneurol.2024.114852. Epub 2024 Jun 8.
In intracerebral hemorrhage (ICH), the mechanical brain injury is a considerable and indispensable factor determining the neurological functions and poor outcomes. Previous studies indicate the mechanically gated ion channel-Piezo1 can transduce mechanical effects following ICH. Isoquercitrin (ISQ) is a well-studied ion channel inhibitor. Furthermore, whether the following Piezo1-mediated neurological impairment can be ameliorated by ISQ remains unclear. Herein, we constructed the hydrostatic pressure model and ICH rat model. Firstly, we found that Piezo1 agonists Yoda1 and Jedi1 facilitated extracellular calcium influx dramatically, but ISQ could depress intracellular Ca overload under hydrostatic pressure in primary neurons. Then we detected the expression profile of Piezo1, NLRP3 and NF-κB p-p65 after ICH, and found that the expression of Piezo1 was much earlier than NLRP3 and NF-κB p-p65. Furthermore, by western blot and immunofluorescence, ISQ decreased the expression of Piezo1 and NLRP3 dramatically like GsMTx4, but Nigericin as a NLRP3 agonist failed to affect Piezo1. Besides, both ISQ and interfering Piezo1 suppressed the upregulated caspase-1, NF-κB p-p65, p-IκBα, Tunel-positive cells and inflammatory factors (IL-1β, IL-6 and TNF-α) in ICH. At last, the hydrostatic pressure or hematoma induced disturbed neural viability, disordered neural cytomorphology, and increased neurobehavioral and cognitive deficits, but they were improved by ISQ and GsMTx4 strongly. Therefore, ISQ could alleviate neurological injuries induced by Piezo1 via NLRP3 pathway. These observations indicated that Piezos might be the new therapeutic targets, and blocking Piezos/NLRP3 pathway by ISQ could be an auspicious strategy for the treatment of ICH.
在脑出血（ICH）中，机械性脑损伤是决定神经功能和预后不良的重要且不可或缺的因素。先前的研究表明，机械门控离子通道-Piezo1 可以在 ICH 后传递机械效应。山柰酚（ISQ）是一种研究较多的离子通道抑制剂。此外，ISQ 是否可以改善 Piezo1 介导的神经损伤尚不清楚。在此，我们构建了液压模型和 ICH 大鼠模型。首先，我们发现 Piezo1 激动剂 Yoda1 和 Jedi1 显著促进细胞外钙内流，但 ISQ 可在原代神经元的液压下抑制细胞内钙超载。然后我们检测了 ICH 后 Piezo1、NLRP3 和 NF-κB p-p65 的表达谱，发现 Piezo1 的表达比 NLRP3 和 NF-κB p-p65 早得多。此外，通过 Western blot 和免疫荧光，ISQ 像 GsMTx4 一样显著降低 Piezo1 和 NLRP3 的表达，但作为 NLRP3 激动剂的 Nigericin 未能影响 Piezo1。此外，ISQ 和干扰 Piezo1 均抑制了 ICH 中上调的 caspase-1、NF-κB p-p65、p-IκBα、Tunel 阳性细胞和炎症因子（IL-1β、IL-6 和 TNF-α）。最后，液压或血肿引起的神经活力紊乱、神经形态紊乱和神经行为及认知功能障碍得到改善，但 ISQ 和 GsMTx4 可显著改善这些损伤。因此，ISQ 可通过 NLRP3 途径减轻 Piezo1 诱导的神经损伤。这些观察结果表明，Piezos 可能是新的治疗靶点，通过 ISQ 阻断 Piezos/NLRP3 途径可能是治疗 ICH 的一种有前途的策略。
