Department of Biopharmaceutical Sciences (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Heilongjiang, China.
Department of Biopharmaceutical Sciences (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Heilongjiang, China.
Brain Res Bull. 2019 Oct;152:117-127. doi: 10.1016/j.brainresbull.2019.07.019. Epub 2019 Jul 17.
Some neuroprotective agents have been used clinically to address the resulting various adverse effects after intracerebral hemorrhage (ICH). Particularly, effectively removing the hematoma is of practical significance to exert neuroprotective effects following ICH. However, such agents are still in need of development. Lithium chloride (LiCl) has shown neuroprotective effects through glycogen synthase kinase-3β (GSK-3β) inhibition in a variety of central nervous system diseases. However, the impact of LiCl on hematoma clearance and the potential molecular mechanisms have not been reported. We hypothesize that LiCl may exert neuroprotective roles after ICH, partly through promoting hematoma resolution. In this study, male Sprague-Dawley rats were subjected to ICH followed by intraperitoneal injection of LiCl (60 mg/kg). The hematoma volumes of ipsilateral hemisphere were determined using Drabkin's method. The sensorimotor deficits were evaluated by neurobehavioral tests. The expressions of target molecules involved in the process of hematoma clearance were assayed using immunofluorescence and Western blot. Our results showed that animals treated with LiCl presented significantly reduced hematoma volume after ICH, which was coupled with enhanced microglia phagocytosis and its differentiation into M2-phenotype within the first 7 days and up-regulated angiogenesis and neurogenesis in the next 7 days. Meanwhile, GSK-3β was inhibited by LiCl and β-catenin became stabilized, which was followed by up-regulation of nuclear factor erythroid 2-related factor 2 and CD36 from days 3 to 7, and increase of vascular endothelial growth factor and brain-derived neurotrophic factor from days 7 to 14. These data suggest that LiCl promotes hematoma resolution via enhancing microglia phagocytosis and M2-phenotype differentiation in the early stage (< 7 days) and angiogenesis and neurogenesis in the chronic phase (days 7-14), thus eventually improving the functional outcomes of ICH rats.
一些神经保护剂已在临床上用于解决脑出血 (ICH) 后产生的各种不良反应。特别是，有效清除血肿对于脑出血后发挥神经保护作用具有实际意义。然而，这些药物仍在开发中。氯化锂 (LiCl) 通过抑制糖原合酶激酶-3β (GSK-3β) 在多种中枢神经系统疾病中显示出神经保护作用。然而，LiCl 对血肿清除的影响及其潜在的分子机制尚未报道。我们假设 LiCl 可能通过促进血肿溶解在脑出血后发挥神经保护作用。在这项研究中，雄性 Sprague-Dawley 大鼠接受 ICH 后，腹腔内注射 LiCl（60mg/kg）。使用 Drabkin 法测定对侧半球血肿体积。通过神经行为测试评估感觉运动缺陷。使用免疫荧光和 Western blot 测定参与血肿清除过程的靶分子的表达。我们的结果表明，用 LiCl 治疗的动物在 ICH 后血肿体积明显减少，这与血肿清除过程中微胶质细胞吞噬作用增强及其在第 7 天分化为 M2 表型以及在第 7 天至第 14 天血管生成和神经发生增加有关。同时，LiCl 抑制 GSK-3β，β-连环蛋白稳定，随后核因子红细胞 2 相关因子 2 和 CD36 从第 3 天到第 7 天上调，血管内皮生长因子和脑源性神经营养因子从第 7 天到第 14 天增加。这些数据表明，LiCl 通过在早期（<7 天）增强小胶质细胞吞噬作用和 M2 表型分化以及在慢性期（7-14 天）促进血管生成和神经发生来促进血肿溶解，从而最终改善脑出血大鼠的功能结局。
