Resource Institute for Chinese & Ethnic Materia Medica, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
Resource Institute for Chinese & Ethnic Materia Medica, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
Phytomedicine. 2023 May;113:154725. doi: 10.1016/j.phymed.2023.154725. Epub 2023 Feb 26.
Regulating the microglial phenotype is an attractive strategy for treating diseases of the central nervous system such as depression and anxiety. Gastrodin can quickly cross the blood-brain barrier and mitigate microglia-mediated inflammation, which widely used to treat a variety of central nervous system diseases associated with microglial dysfunction. However, the molecular mechanism by which gastrodin regulates the functional phenotype of microglia remains unclear.
Since the transcription factor "nuclear factor erythroid 2-related factor 2″ (Nrf2) is associated with the anti-inflammatory effects of gastrodin, we hypothesized that gastrodin induces Nrf2 expression in microglia and thereby programs an anti-inflammatory phenotype.
Male C57BL/6 mice, treated or not with gastrodin, were given lipopolysaccharide (LPS) at 0.25 mg/kg/d for 10 days to induce chronic neuroinflammation. The effects of gastrodin on microglial phenotypes, neuroinflammation and depression- and anxiety-like behaviors were evaluated. In another experiment, animals were treated with Nrf2 inhibitor ML385 throughout the 13-day gastrodin intervention period.
The effects of gastrodin on depression- and anxiety-like behaviors were evaluated through the sucrose preference test, forced swimming test, open field test and elevated plus-maze test; as well as its effects on morphology and molecular and functional phenotypes of hippocampal microglia through immunohistochemistry, real-time PCR and enzyme-linked immunosorbent assays.
Chronic exposure to LPS caused hippocampal microglia to secrete inflammatory cytokines, their somata to enlarge, and their dendrites to lose branches. These changes were associated with depression- and anxiety-like behaviors. Gastrodin blocked these LPS-induced alterations and promoted an Arg-1 microglial phenotype that protected neurons from injury. The effects of gastrodin were associated with Nrf2 activation, whereas blockade of Nrf2 antagonized gastrodin.
These results suggest that gastrodin acts via Nrf2 to promote an Arg-1 microglial phenotype, which buffers the harmful effects of LPS-induced neuroinflammation. Gastrodin may be a promising drug against central nervous system diseases that involve microglial dysfunction.
调节小胶质细胞表型是治疗中枢神经系统疾病（如抑郁症和焦虑症）的一种有吸引力的策略。天麻素可以快速穿过血脑屏障，并减轻小胶质细胞介导的炎症，这广泛用于治疗各种与小胶质细胞功能障碍相关的中枢神经系统疾病。然而，天麻素调节小胶质细胞功能表型的分子机制尚不清楚。
由于转录因子“红细胞生成素 2 相关因子 2”（Nrf2）与天麻素的抗炎作用有关，我们假设天麻素诱导小胶质细胞中 Nrf2 的表达，从而编程抗炎表型。
雄性 C57BL/6 小鼠，用或不用天麻素处理，每天给予 0.25mg/kg/d 的脂多糖（LPS）10 天，以诱导慢性神经炎症。评估天麻素对小胶质细胞表型、神经炎症以及抑郁和焦虑样行为的影响。在另一个实验中，动物在整个 13 天的天麻素干预期间用 Nrf2 抑制剂 ML385 处理。
通过蔗糖偏好试验、强迫游泳试验、旷场试验和高架十字迷宫试验评估天麻素对抑郁和焦虑样行为的影响；通过免疫组织化学、实时 PCR 和酶联免疫吸附试验评估天麻素对海马小胶质细胞形态以及分子和功能表型的影响。
慢性 LPS 暴露导致海马小胶质细胞分泌炎性细胞因子，其胞体增大，树突失去分支。这些变化与抑郁和焦虑样行为有关。天麻素阻断了这些 LPS 诱导的改变，并促进了一种 Arg-1 小胶质细胞表型，保护神经元免受损伤。天麻素的作用与 Nrf2 的激活有关，而 Nrf2 的阻断则拮抗了天麻素。
这些结果表明，天麻素通过 Nrf2 促进 Arg-1 小胶质细胞表型，缓冲 LPS 诱导的神经炎症的有害影响。天麻素可能是一种有前途的治疗涉及小胶质细胞功能障碍的中枢神经系统疾病的药物。
