Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China; Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Henan Engineering Research Center for Prevention and Treatment of Neurodegenerative Diseases, Zhengzhou, 450046, PR China.
J Ethnopharmacol. 2022 Oct 5;296:115491. doi: 10.1016/j.jep.2022.115491. Epub 2022 Jun 23.
LiuweiDihuang (LW) pills was mainly used to treatment of children's fontanelle incomplete closure, enuresis and nervous system development delays and other diseases.Following the deepening of pharmacological research, LW has a good effect on neurological diseases include senile dementia. However, the neuroprotection mechanism of LW on Alzheimer's disease (AD) through regulation of inflammation remains unclear.
Here, we aimed to explore the effects and mechanism of LW on learning and memory deficits in SAMP8 mice.
Mice aged 6 months were treated with LW for 2 months and BV2, C6 and HT22 cells were treated with LW pharmaceutic serum and Lipopolysaccharide (LPS) continuously. Then, cognitive tests were performed, including the Morris water maze and Y maze tests. The mRNA level of cyclooxygenase 2 (COX-2) and pro-inflammatory factors (IL-1β, IL-6 and TNF-α) were examined in cells and the cortex and hippocampus by quantitative RT-PCR. The expression of postsynaptic density protein 95, synaptophysin and various inflammatory factors were detected in the cortex and hippocampus by Western blot. Furthermore, Ionized calcium binding adapter molecule 1, glial fibrillary acidic protein and Aβ were examined in the brain of AD mice by immunofluorescence staining and immunohistochemistry. And synaptic loss and neuronal ultrastructure were observed by transmission electron microscope.
We found that LW suppressed LPS-induced COX-2 expression in vitro. Importantly, LW dramatically improved spatial learning and memory in SAMP8 mice through inhibiting Aβ accumulation and restoring structural synaptic integrity. Furthermore, LW inhibited the glial activation and neuroinflammation (COX-2, IL-1β, IL-6 and TNF-α) in the cortex and hippocampus of SAMP8 mice.
Taken together, the present data not only indicated that LW is an effective agent on improving the learning and memory deficits through mitigating neuroinflammation but highlighted the LW can be a potential therapeutic drug for AD therapy.
六味地黄丸（LW）丸主要用于治疗儿童囟门未闭、遗尿和神经系统发育迟缓等疾病。随着药理学研究的深入，LW 对包括老年痴呆症在内的神经退行性疾病有很好的疗效。然而，LW 通过调节炎症对阿尔茨海默病（AD）的神经保护机制尚不清楚。
本研究旨在探讨 LW 对 SAMP8 小鼠学习记忆障碍的作用及机制。
将 6 月龄小鼠用 LW 处理 2 个月，用 LW 药物血清和脂多糖（LPS）连续处理 BV2、C6 和 HT22 细胞。然后进行认知测试，包括 Morris 水迷宫和 Y 迷宫测试。用定量 RT-PCR 检测细胞及皮质和海马中环氧化酶 2（COX-2）和促炎因子（IL-1β、IL-6 和 TNF-α）的 mRNA 水平。用 Western blot 检测皮质和海马中突触后密度蛋白 95、突触小体蛋白和各种炎症因子的表达。此外，用免疫荧光染色和免疫组织化学法检测 AD 小鼠大脑中的离子钙结合接头分子 1、胶质纤维酸性蛋白和 Aβ。用透射电镜观察突触丢失和神经元超微结构。
我们发现 LW 抑制了体外 LPS 诱导的 COX-2 表达。重要的是，LW 通过抑制 Aβ 积累和恢复结构突触完整性，显著改善 SAMP8 小鼠的空间学习和记忆。此外，LW 抑制了 SAMP8 小鼠皮质和海马中的神经胶质激活和神经炎症（COX-2、IL-1β、IL-6 和 TNF-α）。
综上所述，本研究数据不仅表明 LW 通过减轻神经炎症是一种有效改善学习记忆障碍的药物，而且强调 LW 可能是一种治疗 AD 的潜在治疗药物。
