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

Abstract

Background: Activated 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. Results: Out 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. Conclusions: Based 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.