Abstract
Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.
Highlights
As resident immune cells in the central nervous system, microglia move constantly across brain parenchyma and constitute an immune surveillance system
We recently described a series of a-GalCer analogs containing heterocyclic and phenyl moieties in the sphingosine backbone and found that treatment with a T helper 2 (TH2)-biased a-GalCer analog selectively stimulates the secretion of anti-inflammatory cytokines in invariant natural killer T (iNKT) cells (Figure 1) [25,26]
We demonstrated the anti-inflammatory effect of systematically designed a-GalCer analogs in activated microglia
Summary
As resident immune cells in the central nervous system, microglia move constantly across brain parenchyma and constitute an immune surveillance system. Microglia interact and exchange molecular signals with surrounding neuronal and non-neuronal cells [1]. Microglia are involved in the clearance of damaged neurons by phagocytosis and induce neuronal recovery. Recent studies report that systemic inflammation plays a role in the progression of neurodegenerative diseases by inducing microglial activation [5,6,7]. The development of novel small molecules that can modulate microglial activation has been proposed as one potential strategy for treating or preventing neurodegenerative diseases [8,9]
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