Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, and interrupting the microglial-mediated neuroinflammation has been suggested as a promising strategy to delay or prevent the progression of neurodegeneration. In this study, we investigated the effects of JE-133, an optically active isochroman-2H-chromene conjugate containing a 1,3-disubstituted isochroman unit, on lipopolysaccharide (LPS)-induced microglial neuroinflammation and underlying mechanisms both in vitro and in vivo. First, JE-133 treatment decreased LPS-induced overproduction of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nitrite, and nitric oxide synthase (iNOS) in BV2 microglial cells. Further study revealed that JE-133 downregulated the phosphorylation level of JAK/STAT and upregulated the protein level of Nrf2/HO-1 in LPS-stimulated BV2 microglial cells and verified that JE-133 directly bound to Keap1 by a pull-down assay. Next, JE-133 administration also inhibited neuroinflammation in vivo, as indicated by a reduced CD11b protein level and an overexpressed mRNA level of the pro-inflammatory cytokine TNF-α in the hippocampus of LPS-injected mice. Moreover, the regulative effects of JE-133 on the JAK/STAT and Nrf2/HO-1 pathways were also verified in the hippocampus of LPS-injected mice. Taken together, our study for the first time reports that JE-133 exhibits inhibitory effects against LPS-stimulated neuroinflammation both in vitro and in vivo, which might be associated with the simultaneous regulation of the JAK/STAT and Nrf2 pathways. Our findings may provide important clues for the discovery of effective drug leads/candidates against neuroinflammation-associated neurodegeneration.
Keywords: JAK/STAT; LPS; Nrf2; microglia; neuroinflammation.