Santa-Cecília Flávia V, Socias Benjamin, Ouidja Mohand O, Sepulveda-Diaz Julia E, Acuña Leonardo, Silva Rangel L, Michel Patrick P, Del-Bel Elaine, Cunha Thiago M, Raisman-Vozari Rita
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Av. Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, SP, Brazil.
Neurotox Res. 2016 May;29(4):447-59. doi: 10.1007/s12640-015-9592-2. Epub 2016 Jan 8.
In neurodegenerative diseases, the inflammatory response is mediated by activated glial cells, mainly microglia, which are the resident immune cells of the central nervous system. Activated microglial cells release proinflammatory mediators and neurotoxic factors that are suspected to cause or exacerbate these diseases. We recently demonstrated that doxycycline protects substantia nigra dopaminergic neurons in an animal model of Parkinson's disease. This effect was associated with a reduction of microglial cell activation, which suggests that doxycycline may operate primarily as an anti-inflammatory drug. In the present study, we assessed the anti-inflammatory potential of doxycycline using lipopolysaccharide (LPS)-activated primary microglial cells in culture as a model of neuroinflammation. Doxycycline attenuated the expression of key activation markers in LPS-treated microglial cultures in a concentration-dependent manner. More specifically, doxycycline treatment lowered the expression of the microglial activation marker IBA-1 as well as the production of ROS, NO, and proinflammatory cytokines (TNF-α and IL-1β). In primary microglial cells, we also found that doxycycline inhibits LPS-induced p38 MAP kinase phosphorylation and NF-kB nuclear translocation. The present results indicate that the effect of doxycycline on LPS-induced microglial activation probably occurs via the modulation of p38 MAP kinase and NF-kB signaling pathways. These results support the idea that doxycycline may be useful in preventing or slowing the progression of PD and other neurodegenerative diseases that exhibit altered glia function.
在神经退行性疾病中，炎症反应由活化的胶质细胞介导，主要是小胶质细胞，它们是中枢神经系统的常驻免疫细胞。活化的小胶质细胞释放促炎介质和神经毒性因子，这些因子被怀疑会引发或加剧这些疾病。我们最近证明，强力霉素在帕金森病动物模型中可保护黑质多巴胺能神经元。这种作用与小胶质细胞活化的减少有关，这表明强力霉素可能主要作为一种抗炎药物发挥作用。在本研究中，我们以培养的脂多糖（LPS）激活的原代小胶质细胞作为神经炎症模型，评估了强力霉素的抗炎潜力。强力霉素以浓度依赖的方式减弱了LPS处理的小胶质细胞培养物中关键活化标志物的表达。更具体地说，强力霉素处理降低了小胶质细胞活化标志物IBA-1的表达以及活性氧（ROS）、一氧化氮（NO）和促炎细胞因子（肿瘤坏死因子-α和白细胞介素-1β）的产生。在原代小胶质细胞中，我们还发现强力霉素抑制LPS诱导的p38丝裂原活化蛋白激酶（MAP激酶）磷酸化和核因子-κB（NF-κB）核转位。目前的结果表明，强力霉素对LPS诱导的小胶质细胞活化的作用可能是通过调节p38 MAP激酶和NF-κB信号通路实现的。这些结果支持了强力霉素可能有助于预防或减缓帕金森病和其他表现出胶质细胞功能改变的神经退行性疾病进展的观点。
