Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China.
Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China.
Int Immunopharmacol. 2021 Oct;99:107930. doi: 10.1016/j.intimp.2021.107930. Epub 2021 Jul 3.
Therapeutic strategies used to attenuate inflammation and to increase recovery of neurons after a stroke include microglia anti-inflammatory (M2) polarization and repression of proinflammatory (M1). Extracts isolated from Vaccina variola-inoculated rabbit skin, for example analgecine (AGC), have been used as a therapy for patients experiencing lower back pain associated with degenerative diseases of the spine for about twenty years. In the study presented here, neuroprotective effect associated with AGC was analyzed as well as the anti-inflammatory mechanism linked to AGC in terms of attenuating microglia-mediated neuronal damage. Rats were intravenously injected with AGC after middle cerebral artery occlusion (MCAO), which showed to suppress neuronal loss and reduce neurological deficits. In addition, AGC inhibited pro-inflammatory cytokine release and increased anti-inflammatory cytokines. Furthermore, this study revealed that treatment with AGC supported microglia transition from M1 to M2 in both oxygen-glucose deprivation/reperfusion (OGD/R) and LPS/IFN-γ induced microglia cells, as well as indirectly inhibited LPS/IFN-γ-induced neuronal damage through the modulation of microglial polarization. It is also important to note that AGC inhibited NF-κB p65 phosphorylation through repressing TLR4/Myd88/TRAF6 signaling pathway. In addition, we found that TLR4 inhibition by AGC depended on Myd88. Altogether, this work supports that AGC inhibits M1 microglial polarization and promotes anti-inflammation independently and dependently on TLR4/MyD88. Since it is shown to have neuroprotective effects in this study, AGC has great potential to be used in the clinic to reduce inflammation and aid in recovery after stroke.
用于减轻炎症和增加中风后神经元恢复的治疗策略包括小胶质细胞抗炎（M2）极化和抑制促炎（M1）。例如，从接种牛痘兔皮肤中分离出的提取物analgecine（AGC）已被用作治疗患有与脊柱退行性疾病相关的下腰痛的患者的治疗方法已有大约二十年的历史。在本研究中，分析了 AGC 相关的神经保护作用以及与 AGC 相关的抗炎机制，即减轻小胶质细胞介导的神经元损伤。在大脑中动脉闭塞（MCAO）后，大鼠静脉内注射 AGC，结果表明其可抑制神经元丢失并减少神经功能缺损。此外，AGC 抑制促炎细胞因子的释放并增加抗炎细胞因子。此外，这项研究表明，AGC 治疗支持小胶质细胞从 M1 向 M2 的转变，在氧葡萄糖剥夺/再灌注（OGD / R）和 LPS / IFN-γ诱导的小胶质细胞中均如此，并且通过调节小胶质细胞极化间接抑制 LPS / IFN-γ诱导的神经元损伤。同样重要的是要注意，AGC 通过抑制 TLR4 / MyD88 / TRAF6 信号通路来抑制 NF-κB p65 磷酸化。此外，我们发现 AGC 通过抑制 TLR4 依赖于 MyD88。总之，这项工作支持 AGC 独立地并依赖于 TLR4 / MyD88 抑制 M1 小胶质细胞极化和促进抗炎。由于在本研究中显示出神经保护作用，因此 AGC 具有很大的潜力在临床上用于减轻炎症并帮助中风后恢复。
