Regulation of neuroinflammation by matrix metalloproteinase-8 inhibitor derivatives in activated microglia and astrocytes
Autor: | Ji Woong Choi, Hee Sun Kim, Min-Ji Choi, Bhakta Prasad Gaire, Eun Jung Lee, Gyeongjin Lee |
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Rok vydání: | 2017 |
Předmět: |
musculoskeletal diseases
0301 basic medicine animal structures microglia Matrix metalloproteinase neuroinflammation Proinflammatory cytokine 03 medical and health sciences fluids and secretions 0302 clinical medicine Gene expression medicine Neuroinflammation systemic inflammation Microglia Kinase business.industry astrocytes musculoskeletal system medicine.disease Astrogliosis Cell biology carbohydrates (lipids) 030104 developmental biology medicine.anatomical_structure Oncology Immunology MMP-8 inhibitor Tumor necrosis factor alpha business 030217 neurology & neurosurgery Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | Matrix metalloproteinases (MMPs) play a pivotal role in neuroinflammation that is associated with neurodegenerative diseases. Our group recently reported that MMP-8 mediates inflammatory reactions by modulating the processing of TNF-α. To improve the efficacy of the currently available MMP-8 inhibitor (M8I), we have synthesized structurally modified M8I derivatives (comp 2, 3, 4, 5) and compared their efficacy with original compound (comp 1). Among M8I derivatives, comp 2, 3, and 5 inhibited the production of NO, ROS, and IL-6 more efficiently than the original compound in lipopolysaccharide (LPS)-stimulated microglia. When we compared the anti-inflammatory mechanisms of the most effective derivative, comp 3, with comp 1, comp 3 suppressed the mRNA expression of iNOS and cytokines more efficiently than comp 1. Although comp 1 inhibits only TNF-α processing, comp 3 additionally inhibits the expression of TNF-α. Both compounds inhibited LPS-induced activity of MAP kinases, NF-κB, and AP-1, while they increased heme oxygenase-1 expression by upregulating AMPK-Nrf2 signaling. Overall, the effect of comp 3 on anti-inflammatory signaling was much stronger than comp 1. We verified the anti-inflammatory effects of comp 1 and 3 in the LPS-injected mouse brain and primary cultured astrocytes. Comp 1 and 3 suppressed microglial activation, astrogliosis, and proinflammatory gene expression in the brain. Moreover, the compounds inhibited proinflammatory gene expression in the cultured astrocytes. Collectively, our data suggest that the MMP-8 inhibitor may be a promising therapeutic agent for neuroinflammatory disorders. |
Databáze: | OpenAIRE |
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