Park Joon, Kim Yun Tai
Division of Functional Food Research, Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Korea.
Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Korea.
Antioxidants (Basel). 2020 Jul 16;9(7):626. doi: 10.3390/antiox9070626.
Microglial activation-mediated neuroinflammation influences the development of inflammatory pain. The aim of this study was to investigate the anti-inflammatory effects and mechanisms of aqueous extract (EJE) in microglia activation-mediated inflammatory pain. EJE was found to suppress lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), ionized calcium-binding adapter molecule 1 (IBA-1), and pro-inflammatory cytokines in BV2 microglial cells. In addition, LPS-induced c-Jun NH terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation were inhibited by EJE. Intriguingly, EJE also inhibited p65 phosphorylation by activating extracellular signal-regulated kinase-1/2 (ERK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Furthermore, the effects of EJE treatment, such as HO-1 induction and the reduction of NF-ĸB activation, were reversed by ERK1/2 inhibition. In an inflammatory pain mouse model, Complete Freund's Adjuvant (CFA)-induced mechanical allodynia and foot swelling were alleviated by the oral administration of EJE. Consistent with in vitro results, EJE increased HO-1, while decreasing CFA-induced COX-2, IBA-1, and pro-inflammatory cytokines in the spinal cord. Among the components of EJE, butanol most heavily suppressed LPS-induced microglial activation and increased HO-1 expression. These findings indicate that EJE can alleviate inflammatory pain by inhibiting p38 and JNK and by suppressing NF-ĸB via ERK/Nrf2/HO-1 signaling.
小胶质细胞激活介导的神经炎症影响炎性疼痛的发展。本研究旨在探讨水提取物（EJE）在小胶质细胞激活介导的炎性疼痛中的抗炎作用及其机制。研究发现，EJE可抑制脂多糖（LPS）诱导的BV2小胶质细胞中诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）、离子钙结合衔接分子1（IBA-1）和促炎细胞因子的表达。此外，EJE可抑制LPS诱导的c-Jun氨基末端蛋白激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）的磷酸化。有趣的是，EJE还可通过激活细胞外信号调节激酶-1/2（ERK）/核因子红细胞2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）信号通路来抑制p65的磷酸化。此外，ERK1/2抑制可逆转EJE处理的效果，如HO-1的诱导和NF-κB激活的减少。在炎性疼痛小鼠模型中，口服EJE可减轻完全弗氏佐剂（CFA）诱导的机械性异常性疼痛和足部肿胀。与体外实验结果一致，EJE可增加脊髓中HO-1的表达，同时降低CFA诱导的COX-2、IBA-1和促炎细胞因子的表达。在EJE的成分中，丁醇对LPS诱导的小胶质细胞激活的抑制作用最强，并可增加HO-1的表达。这些研究结果表明，EJE可通过抑制p38和JNK以及通过ERK/Nrf2/HO-1信号通路抑制NF-κB来减轻炎性疼痛。
