Xu Zhixiang, Wu Jing, Zheng Jiyue, Ma Haikuo, Zhang Hongjian, Zhen Xuechu, Zheng Long Tai, Zhang Xiaohu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China.
Int Immunopharmacol. 2015 Apr;25(2):528-37. doi: 10.1016/j.intimp.2015.02.033. Epub 2015 Mar 10.
Neuroinflammation is involved in the process of several central nervous system (CNS) diseases such as Parkinson's disease, Alzheimer's disease, ischemia and multiple sclerosis. As the macrophages in the central nervous system, microglial cell function in the innate immunity of the brain and are largely responsible for the inflammation-mediated neurotoxicity. Prevention of microglia activation might alleviate neuronal damage and degeneration under the inflammatory conditions, and therefore, represents a possible therapeutic approach to the aforementioned CNS diseases. Here we report the synthesis of a number of non-steroidal anti-inflammatory drug (NSAID) conjugates, and the evaluation of their anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and primary mouse microglial cells. Among the tested analogues, compounds 8 and 11 demonstrated potent inhibition of nitric oxide production with no or weak cell toxicity. Compound 8 also significantly suppressed the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, cyclooxygenase (COX)-2 as well as inducible nitric oxide synthase (iNOS) in LPS-stimulated BV-2 microglial cells. Further mechanistic studies indicated that compound 8 significantly suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and subsequent activation of activator of transcription 1 (AP-1). Furthermore, in a co-culture system, compound 8 inhibited the cytotoxicity generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Collectively, these experimental results demonstrated that compound 8 possessed potent anti-neuroinflammatory activity via inhibition of microglia activation, and might serve as a potential lead for the therapeutic treatment of neuroinflammatory diseases.
神经炎症参与了多种中枢神经系统（CNS）疾病的发病过程，如帕金森病、阿尔茨海默病、缺血性疾病和多发性硬化症。作为中枢神经系统中的巨噬细胞，小胶质细胞在大脑的固有免疫中发挥作用，并且在很大程度上介导炎症相关的神经毒性。预防小胶质细胞激活可能会减轻炎症条件下的神经元损伤和退变，因此，这代表了一种针对上述中枢神经系统疾病的潜在治疗方法。在此，我们报告了一系列非甾体抗炎药（NSAID）缀合物的合成，并评估了它们在脂多糖（LPS）刺激的BV-2小胶质细胞和原代小鼠小胶质细胞中的抗炎作用。在所测试的类似物中，化合物8和11表现出对一氧化氮产生的强效抑制作用，且无细胞毒性或细胞毒性较弱。化合物8还显著抑制了LPS刺激的BV-2小胶质细胞中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、环氧化酶（COX）-2以及诱导型一氧化氮合酶（iNOS）的表达。进一步的机制研究表明，化合物8显著抑制丝裂原活化蛋白激酶（MAPK）的磷酸化以及随后转录激活因子1（AP-1）的激活。此外，在共培养系统中，化合物8抑制了LPS激活的小胶质细胞对HT-22神经母细胞瘤细胞产生的细胞毒性。总体而言，这些实验结果表明化合物8通过抑制小胶质细胞激活具有强效的抗神经炎症活性，可能作为神经炎症性疾病治疗的潜在先导药物。
