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Regulation of neuroinflammation by matrix metalloproteinase-8 inhibitor derivatives in activated microglia and astrocytes
- Title
- Regulation of neuroinflammation by matrix metalloproteinase-8 inhibitor derivatives in activated microglia and astrocytes
- Authors
- Lee E.-J.; Choi M.-J.; Lee G.; Gaire B.P.; Choi J.W.; Kim H.-S.
- Ewha Authors
- 김희선
- SCOPUS Author ID
- 김희선
- Issue Date
- 2017
- Journal Title
- Oncotarget
- ISSN
- 1949-2553
- Citation
- Oncotarget vol. 8, no. 45, pp. 78677 - 78690
- Keywords
- Astrocytes; Microglia; MMP-8 inhibitor; Neuroinflammation; Systemic inflammation
- Publisher
- Impact Journals LLC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- 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. © Lee et al.
- DOI
- 10.18632/oncotarget.20207
- Appears in Collections:
- 의과대학 > 의학과 > Journal papers
- Files in This Item:
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