Department of Neurosurgery, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing 210029, Jiangsu, China.
Department of Ophthalmology, Third Medical Center of Chinese, PLA General Hospital, Beijing 100000, China.
Exp Neurol. 2024 Jul;377:114777. doi: 10.1016/j.expneurol.2024.114777. Epub 2024 Apr 16.
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating acute cerebrovascular event with high mortality and permanent disability rates. Higher galectin-3 levels on days 1-3 have been shown to predict the development of delayed cerebral infarction or adverse outcomes after SAH. Recent single-cell analysis of microglial transcriptomic diversity in SAH revealed that galectin could influence the development and course of neuroinflammation after SAH.
This study aimed to investigate the role and mechanism of galectin-3 in SAH and to determine whether galectin-3 inhibition prevents early brain injury by reducing microglia polarization using a mouse model of SAH and oxyhemoglobin-treated activation of mouse BV2 cells in vitro.
We found that the expression of galectin-3 began to increase 12 h after SAH and continued to increase up to 72 h. Importantly, TD139-inhibited galectin-3 expression reduced the release of inflammatory factors in microglial cells. In the experimental SAH model, TD139 treatment alleviated neuroinflammatory damage after SAH and improved defects in neurological functions. Furthermore, we demonstrated that galectin-3 inhibition affected the activation and M1 polarization of microglial cells after SAH. TD139 treatment inhibited the expression of TLR4, p-NF-κB p65, and NF-κB p65 in microglia activated by oxyhemoglobin as well as eliminated the increased expression and phosphorylation of JAK2 and STAT3.
These findings suggest that regulating microglia polarization by galectin-3 after SAH to improve neuroinflammation may be a potential therapeutic target.
蛛网膜下腔出血（SAH）是一种具有高死亡率和永久性残疾率的破坏性急性脑血管事件。第 1-3 天较高的半乳糖凝集素-3 水平已被证明可预测 SAH 后迟发性脑梗死或不良结局的发生。最近对 SAH 中小胶质细胞转录组多样性的单细胞分析表明，半乳糖凝集素可能影响 SAH 后神经炎症的发展和进程。
本研究旨在探讨半乳糖凝集素-3 在 SAH 中的作用和机制，并通过使用 SAH 小鼠模型和体外氧合血红蛋白处理的小鼠 BV2 细胞激活来确定半乳糖凝集素-3 抑制是否通过减少小胶质细胞极化来预防早期脑损伤。
我们发现，半乳糖凝集素-3 的表达在 SAH 后 12 小时开始增加，并持续增加至 72 小时。重要的是，TD139 抑制半乳糖凝集素-3 的表达减少了小胶质细胞中炎症因子的释放。在实验性 SAH 模型中，TD139 治疗减轻了 SAH 后的神经炎症损伤，并改善了神经功能缺陷。此外，我们证明半乳糖凝集素-3 抑制影响了 SAH 后小胶质细胞的激活和 M1 极化。TD139 治疗抑制了氧合血红蛋白激活的小胶质细胞中 TLR4、p-NF-κB p65 和 NF-κB p65 的表达，并消除了 JAK2 和 STAT3 的增加表达和磷酸化。
这些发现表明，通过 SAH 后调节半乳糖凝集素-3 来改善神经炎症可能是一种潜在的治疗靶点。
