Sonidegib Suppresses Production of Inflammatory Mediators and Cell Migration in BV2 Microglial Cells and Mice Treated with Lipopolysaccharide via JNK and NF-κB Inhibition.
Ngoc Minh NguyenMen Thi Hoai DuongBich Phuong BuiPhuong Linh NguyenXiaozhen ChenJungsook ChoHee Chul AhnPublished in: International journal of molecular sciences (2022)
Our structure-based virtual screening of the FDA-approved drug library has revealed that sonidegib, a smoothened antagonist clinically used to treat basal cell carcinoma, is a potential c-Jun N-terminal kinase 3 (JNK3) inhibitor. This study investigated the binding of sonidegib to JNK3 via 19 F NMR and its inhibitory effect on JNK phosphorylation in BV2 cells. Pharmacological properties of sonidegib to exert anti-inflammatory and anti-migratory effects were also characterized. We found that sonidegib bound to the ATP binding site of JNK3 and inhibited JNK phosphorylation in BV2 cells, confirming our virtual screening results. Sonidegib also inhibited the phosphorylation of MKK4 and c-Jun, the upstream and downstream signals of JNK, respectively. It reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO), and the expression of inducible NO synthase and cyclooxygenase-2. The LPS-induced cell migration was suppressed by sonidegib. Sonidegib inhibited the LPS-induced IκBα phosphorylation, thereby blocking NF-κB nuclear translocation. Consistent with these findings, orally administered sonidegib attenuated IL-6 and TNF-α levels in the brains of LPS-treated mice. Collectively, our results indicate that sonidegib suppresses inflammation and cell migration in LPS-treated BV2 cells and mice by inhibiting JNK and NF-κB signaling. Therefore, sonidegib may be implicated for drug repurposing to alleviate neuroinflammation associated with microglial activation.
Keyphrases
- lps induced
- induced apoptosis
- inflammatory response
- signaling pathway
- cell migration
- endoplasmic reticulum stress
- oxidative stress
- cell death
- cell cycle arrest
- pi k akt
- lipopolysaccharide induced
- nitric oxide
- anti inflammatory
- toll like receptor
- magnetic resonance
- rheumatoid arthritis
- poor prognosis
- protein kinase
- single cell
- subarachnoid hemorrhage
- high resolution
- nitric oxide synthase
- type diabetes
- metabolic syndrome
- spinal cord
- tyrosine kinase
- insulin resistance
- risk assessment
- binding protein
- basal cell carcinoma
- newly diagnosed
- human health
- solid state
- climate change