propane-2-sulfonic-acid-octadec-9-enyl-amide and Inflammation

Our previous study showed that propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator-activated receptor α and γ (PPARα/γ) dual agonist, inhibits inflammatory responses in tumor necrosis factor alpha (TNFα)-induced vascular endothelial cells or lipopolysaccharide (LPS)-induced human myeloid leukemia mononuclear cells-1. However, little is known about whether N15 applies to other pathological or neuroinflammatory conditions. In the present study, we detected the effect of N15 on the LPS-induced neuroinflammatory response in mice and further investigated whether the effect of N15 on neuroinflammation and neuronal cells survival was related to PPARα/γ dual pathways. We found that N15 decreased the mRNA expression of the proinflammatory cytokines IL-1β, IL-6, TNFα, inducible nitric oxide synthase and cyclooxygenase-2; inhibited microglial activation; and ameliorated neuronal apoptosis in the hippocampus and cortex of LPS-induced mice. In addition, PPARα antagonist MK886 or PPARγ antagonist T0070907 partially eliminated the effect of N15. These results demonstrate that N15 exerts an anti-inflammatory effect, at least in part, by enhancing PPARα/γ dual signaling. Our study reveals that N15 may be a promising neuronal protective drug for the treatment of neuroinflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; PPAR alpha; PPAR gamma; Sulfonic Acids

Our group synthesized propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator activated receptor alpha (PPARα) agonist. Because PPARα activation is associated with inflammation control, we hypothesize that N15 may have anti-inflammatory effects. We investigated the effect of N15 on the regulation of inflammation in THP-1 cells stimulated with lipopolysaccharide (LPS). In particular, we assessed the production of chemokines, adhesion molecules and proinflammatory cytokines, three important types of cytokines that are released from monocytes and are involved in the development of atherosclerosis. The results showed that N15 remarkably reduced the mRNA expression of chemokines, such as monocyte chemotactic protein 1 (MCP-1 or CCL2), interleukin-8 (IL-8) and interferon-inducible protein-10 (IP-10 or CXCL10), and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). N15 also decreased the protein expression of vascular cell adhesion molecule (VCAM) and matrix metalloproteinase (MMP) 2 and 9. The reduction in the expression of cytokine mRNAs observed following N15 treatment was abrogated in THP-1 cells treated with PPARα siRNA, indicating that the anti-inflammatory effects of N15 are dependent on PPARα activation. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) inhibition, which are dependent on PPARα activation, were also involved in the mechanism underlying the anti-inflammatory effects of N15. In conclusion, the novel PPARα agonist, N15, exerts notable anti-inflammatory effects, which are mediated via PPARα activation and TLR4/NF-κB and STAT3 inhibition, in LPS-stimulated THP-1 cells. In our study, N15 exhibits promise for the treatment of atherosclerosis.

Topics: Anti-Inflammatory Agents; Cell Survival; Chemokines; Fenofibrate; Humans; Inflammation; Lipopolysaccharides; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Monocytes; NF-kappa B; PPAR alpha; Signal Transduction; STAT3 Transcription Factor; Sulfonic Acids; Toll-Like Receptor 4; Vascular Cell Adhesion Molecule-1