Abstract
The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR spectroscopy indicated its direct binding to the ATP-binding site of JNK3, validating our observations. Although the antihistamine effect of Aze is well documented, the involvement of the JNK pathway in its action remains to be elucidated. This study investigated the effects of Aze on lipopolysaccharide (LPS)-induced JNK phosphorylation, pro-inflammatory mediators, and cell migration in BV2 microglial cells. Aze was found to inhibit the LPS-induced phosphorylation of JNK and c-Jun. It also inhibited the LPS-induced production of pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and nitric oxide. Wound healing and transwell migration assays indicated that Aze attenuated LPS-induced BV2 cell migration. Furthermore, Aze inhibited LPS-induced IκB phosphorylation, thereby suppressing nuclear translocation of NF-κB. Collectively, our data demonstrate that Aze exerts anti-inflammatory and anti-migratory effects through inhibition of the JNK/NF-κB pathway in BV2 cells. Based on our findings, Aze may be a potential candidate for drug repurposing to mitigate neuroinflammation in various neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases.
Highlights
Neuroinflammation is described as an innate immune response of the cells in the central nervous systems (CNS) to cope with infection and eliminate pathogens, cell debris, and/or misfolded proteins [1,2]
Cell-based experiments illustrated that this drug suppressed the phosphorylation of Jun N-terminal kinases (JNKs) and subsequently blocked the phosphorylation of its downstream transcription factor c-Jun in LPS-treated BV2 cells
The activation of JNKs is a critical player in immune response, which is associated with the pathogenesis of many neurological and immunological disorders
Summary
Neuroinflammation is described as an innate immune response of the cells in the central nervous systems (CNS) to cope with infection and eliminate pathogens, cell debris, and/or misfolded proteins [1,2]. It has been reported that the total amount of nuclear JNKs and the phosphorylation of the transcription factor c-Jun are rapidly and transiently increased in the lipopolysaccharide (LPS)-stimulated microglial cells, leading to augmented levels of inducible NO synthase (iNOS) and pro-inflammatory mediators such as interleukin-6 (IL-6) and NO [12,14,15]. These findings indicate that JNKs play crucial roles in the neuroinflammatory processes underlying various neurodegenerative disorders; JNK inhibitors may offer a promising therapeutic approach for the treatment of these diseases. We employed LPS-treated BV2 cells, a murine microglial cell line, as a model to investigate the anti-inflammatory and anti-migratory properties of Aze and to elucidate the signaling molecules mediating its effects
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