期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 25, 期 2, 页码 528-537出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2015.02.033
关键词
Neuroinflammation; Neurodegenerative diseases; Microglia activation; Drug conjugates; Neuroprotection
资金
- National Natural Science Foundation of China [81273372, 81372688, 81473090, 81130023, 31373382]
- National Basic Research Plan (973) of the Ministry of Science and Technology of China [2011CB5C4403]
- China Postdoctoral Science Foundation [2013M541729]
- Natural Science Foundation of Jiangsu Province [BK20140313, BM2013003]
- PAPD (A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions)
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)-alpha, 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. (C) 2015 Elsevier B.V. All rights reserved.
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