N,N-disubstituted azines attenuate LPS-mediated neuroinflammation in microglia and neuronal apoptosis via inhibiting MAPK signaling pathways

BMC Neuroscience

Research Article

Sun Yeou Kim¹  Lalita Subedi¹  Chaeho Pak¹  Hakwon Kim²  Goeun Lee²  Kangwoo Lee²  Oh Wook Kwon³ 

[1] College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, 21936, Incheon, Republic of Korea;Department of Applied Chemistry and Institute of Natural Sciences, Kyung Hee University, Global Campus, #1732 Deogyeong-daero, Giheung-gu, 446-701, Yongin, Gyenggi-do, Republic of Korea;Graduate School of East-West Medical Science, Kyung Hee University, Global Campus, #1732 Deogyeong-daero, Giheung-gu, 446-701, Yongin, Gyeonggi-do, Republic of Korea;

关键词: Azine;    Lipopolysaccharide;    Neuroinflammation;    MAPK;    Apoptosis;   

DOI  :  10.1186/s12868-017-0399-3

 received in 2017-05-19, accepted in 2017-12-13,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundActivated microglia interact with astrocytes and neuronal cells to induce neuroinflammation, which can contribute to the pathogenesis and progression of Alzheimer’s and Parkinson’s disease. To identify the most effective anti-neuroinflammatory agent, we designed and synthesized a family of 13 new azine derivatives and investigated their anti-neuroinflammatory activities in LPS-activated BV-2 microglial cells.ResultsOut of 13 derivatives, compound 3 [4,4′-(1E,1′E,3E,3′E)-3,3′-(hydrazine-1,2-diylidene) bis-(prop-1-ene-1-yl-3-ylidene) bis-(2-methoxyphenol)] exhibited excellent anti-neuroinflammatory activities (IC50 = 12.47 µM), which protected neurons from microglia-mediated neurotoxicity. Specifically, the anti-neuroinflammatory effects of compound 3 inhibited MAPK signaling pathways through the inhibition of p38 and JNK mediated signaling and the production of pro-inflammatory cytokines, and inflammatory mediators. Additionally, compound 3 strongly exhibited neuroprotective effect by inhibiting LPS-mediated necrosis and apoptosis. Preliminary SAR analysis suggests that the presence of methoxyphenol and the substitution pattern within hydrazine may influence the anti-neuroinflammatory activity. FACS analysis also strongly supports the neuroprotective effect of compound 3.ConclusionsBased on our results, the compound 3 exhibited excellent anti-neuroinflammatory activity against LPS-activated microglia, which resulted in the inhibition of neuronal apoptosis and neuronal degeneration.

【 授权许可】

CC BY   
© The Author(s) 2017