Department of Neurology and Stroke Centre, the First Affiliated Hospital of Jinan University, Guangzhou, China.
Department of Oncology, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.
Int Immunopharmacol. 2023 Oct;123:110698. doi: 10.1016/j.intimp.2023.110698. Epub 2023 Jul 28.
Intracerebral hemorrhage (ICH) can result in secondary brain injury due to inflammation and breakdown of the blood-brain barrier (BBB), which are closely associated with patient prognosis. The potential of the heat shock protein 90 (Hsp90) inhibitor 17-DMAG in promoting neuroprotection has been observed in certain vascular diseases. However, the precise role of 17-DMAG treatment in ICH is not yet fully understood. In this study, we found that treatment with 17-DMAG (5 mg/kg) effectively reduced hematoma expansion and resulted in improved neurological outcomes. Meanwhile, the injection of 17-DMAG had a positive effect on reducing BBB disruption in rats with ICH. This effect was achieved by increasing the levels of BBB tight junction proteins (TJPs) such as zo-1, claudin-5, and occludin. As a result, the leakage of EB extravasation, brain edema and IgG in the peri-hematoma tissue were reduced. Furthermore, the injection of 17-DMAG decreased the infiltration of neutrophils into the brain tissues surrounding the hematoma in ICH rats and also reduced the production of proinflammatory cytokines IL-6 and TNF-α. Next, we used integrative mass spectrometry (MS) and molecular docking analysis to confirm that sex determining region Y-box protein 5 (SOX5) is a potential direct target of 17-DMAG in ICH. SOX5 encodes a positive regulator of the PI3K/Akt axis, and treatment with 17-DMAG resulted in a noticeable increase in SOX5 accumulation. To further investigate the role of SOX5, we employed virus-regulated SOX5 silencing and found that suppressing SOX5 blocked the ability of 17-DMAG to suppress neutrophil trafficking. Additionally, silencing SOX5 blocked the protective effects of 17-DMAG on the BBB by inhibiting PI3K, p-Akt, and BBB TJPs levels, which led to an increase in EB and IgG leakage in the peri-hematoma tissue after ICH. Similarly, when SOX5 was knocked down, the protective effects of 17-DMAG were lost. Overall, the results of our study indicate that the injection of 17-DMAG has the potential to mitigate neuroinflammation and prevent the disruption of the BBB caused by ICH, resulting in improved neurological outcomes in rats. These positive effects are attributed to the regulation of SOX5 and activation of the PI3K/Akt pathway. These findings highlight the possibility of targeting SOX5 and the PI3K/Akt pathway as a novel therapeutic approach for ICH.
脑出血（ICH）可导致炎症和血脑屏障（BBB）破裂引起的继发性脑损伤，这与患者的预后密切相关。热休克蛋白 90（Hsp90）抑制剂 17-DMAG 在某些血管疾病中具有促进神经保护的潜力。然而，17-DMAG 治疗 ICH 的确切作用尚未完全阐明。在这项研究中，我们发现，用 17-DMAG（5mg/kg）治疗可有效减少血肿扩大，改善神经功能结局。同时，17-DMAG 注射对减少 ICH 大鼠 BBB 破坏有积极作用。这一作用是通过增加 BBB 紧密连接蛋白（TJPs）的水平来实现的，如 zo-1、claudin-5 和 occludin。结果，伊文思蓝（EB）外渗、脑血周围组织水肿和 IgG 的漏出减少。此外，17-DMAG 注射减少了 ICH 大鼠血肿周围脑组织中中性粒细胞的浸润，并降低了促炎细胞因子 IL-6 和 TNF-α的产生。接下来，我们使用整合质谱（MS）和分子对接分析证实性别决定区 Y 框蛋白 5（SOX5）是 17-DMAG 在 ICH 中的一个潜在直接靶点。SOX5 编码 PI3K/Akt 轴的正调控因子，用 17-DMAG 治疗后，SOX5 积累明显增加。为了进一步研究 SOX5 的作用，我们采用病毒调节的 SOX5 沉默，并发现抑制 SOX5 阻断了 17-DMAG 抑制中性粒细胞迁移的能力。此外，沉默 SOX5 通过抑制 PI3K、p-Akt 和 BBB TJPs 水平，阻断了 17-DMAG 对 BBB 的保护作用，导致 ICH 后血周围组织中 EB 和 IgG 的漏出增加。同样，当 SOX5 被敲除时，17-DMAG 的保护作用丧失。总的来说，我们的研究结果表明，17-DMAG 注射具有减轻神经炎症和防止 ICH 引起的 BBB 破坏的潜力，从而改善大鼠的神经功能结局。这些积极的影响归因于 SOX5 的调节和 PI3K/Akt 途径的激活。这些发现强调了靶向 SOX5 和 PI3K/Akt 途径作为 ICH 新的治疗方法的可能性。
