Huang Chao, Wang Jili, Lu Xu, Hu Wenfeng, Wu Feng, Jiang Bo, Ling Yong, Yang Rongrong, Zhang Wei
Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, China.
Department of Anesthesiology, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong, Jiangsu Province 226001, China.
Neurosci Lett. 2016 Apr 21;619:34-42. doi: 10.1016/j.neulet.2016.02.021. Epub 2016 Feb 12.
Induction of pro-inflammatory factors is one of the characteristics of microglial activation and can be regulated by numerous active agents extracted from plants. Suppression of pro-inflammatory factors is beneficial to alleviate neuroinflammation. Z-guggulsterone, a compound extracted from the gum resin of the tree commiphora mukul, exhibits numerous anti-inflammatory effects. However, the role and mechanism of Z-guggulsterone in pro-inflammatory responses in microglia remains unclear. This study addressed this issue in in vitro murine microglia and in vivo neuroinflammation models. Results showed that Z-guggulsterone reduced inducible nitric oxide (iNOS) protein expression as well as nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production in LPS-stimulated BV-2 cells. Z-guggulsterone also reduced the mRNA level of iNOS, TNF-α, and IL-6. Mechanistic studies revealed that Z-guggulsterone attenuated the LPS-induced degradation of inhibitor κ B-α (IκB-α) as well as the LPS-induced nuclear translocation of nuclear factor-κB (NF-κB). Z-guggulsterone, however, failed to reduce the LPS-induced increase in NF-κB phosphorylation level. These major findings were ascertained in primary microglia where the LPS-induced increases in iNOS expression, NO content, and IκB-α degradation were diminished by Z-guggulsterone treatment. In a mouse model of neuroinflammation, Z-guggulsterone exhibited significant anti-inflammatory effects, which were exemplified by the attenuation of microglial activation and neuroinflammation-induced behavioral abnormalities in Z-guggulsterone-treated mice. Taken together, these studies demonstrate that Z-guggulsterone attenuates the LPS-mediated induction of pro-inflammatory factors in microglia via inhibition of IκB-α-NF-κB signals, providing evidence to uncover the potential role of Z-guggulsterone in neuroinflammation-associated disorder therapies.
促炎因子的诱导是小胶质细胞激活的特征之一，并且可被从植物中提取的多种活性剂调节。抑制促炎因子有利于减轻神经炎症。Z-古芸烯酮是从没药树的树胶脂中提取的一种化合物，具有多种抗炎作用。然而，Z-古芸烯酮在小胶质细胞促炎反应中的作用和机制仍不清楚。本研究在体外小鼠小胶质细胞和体内神经炎症模型中探讨了这个问题。结果表明，Z-古芸烯酮降低了脂多糖刺激的BV-2细胞中诱导型一氧化氮合酶（iNOS）蛋白表达以及一氧化氮（NO）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的产生。Z-古芸烯酮还降低了iNOS、TNF-α和IL-6的mRNA水平。机制研究表明，Z-古芸烯酮减弱了脂多糖诱导的抑制蛋白κB-α（IκB-α）降解以及脂多糖诱导的核因子κB（NF-κB）核转位。然而，Z-古芸烯酮未能降低脂多糖诱导的NF-κB磷酸化水平的升高。这些主要发现也在原代小胶质细胞中得到证实，在原代小胶质细胞中，Z-古芸芸烯酮处理减少了脂多糖诱导的iNOS表达增加、NO含量增加和IκB-α降解。在神经炎症小鼠模型中，Z-古芸烯酮表现出显著的抗炎作用，这体现在Z-古芸烯酮处理的小鼠中，小胶质细胞激活和神经炎症诱导的行为异常得到减轻。综上所述，这些研究表明，Z-古芸烯酮通过抑制IκB-α-NF-κB信号减弱了脂多糖介导的小胶质细胞中促炎因子的诱导，为揭示Z-古芸烯酮在神经炎症相关疾病治疗中的潜在作用提供了证据。
