article · Scientific Reports
Amlexanox is an established anti-inflammatory drug used for conditions such as asthma, allergic rhinitis, and ulcers. Research demonstrates its potential application in targeting neuroinflammation, a driver of neurodegenerative disorders. In laboratory tests using an endotoxin-induced model, amlexanox administration reduced levels of the kinase IKKε, suppressed microglial activation, and lowered pro-inflammatory cytokines in vivo. In cell cultures comprising murine macrophages, murine microglia, and human microglial lines, the compound consistently diminished pro-inflammatory mediators and chemokines. Mechanistic evaluations showed that this anti-inflammatory activity operates by downregulating the NF-κB and STAT3 signalling pathways. Furthermore, combining amlexanox with a selective STAT3 inhibitor produced enhanced suppression of neurotoxic and inflammatory signals. These findings indicate that repurposing amlexanox, either independently or alongside targeted signalling inhibitors, offers a plausible route for treating neuroinflammatory and neurodegenerative conditions.
Neuroinflammation contributes heavily to the progression of neurodegenerative diseases. Because amlexanox is already clinically approved for other inflammatory ailments, demonstrating its ability to protect brain immune cells and reduce neurotoxic molecules provides a grounded foundation for drug repurposing. Repurposing established compounds can shorten the timeline needed to develop interventions for complex brain disorders.
The findings could inform the development of repurposed therapeutic formulations for pharmaceutical developers targeting neuroinflammatory and neurodegenerative disorders. Combining amlexanox with STAT3 inhibitors presents an additional pathway for combination therapies. Because testing remains at the preclinical stage, using laboratory cell cultures and animal models, the research is at an early phase requiring further clinical validation and pharmacokinetic evaluation before real-world adoption.
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Amlexanox is an anti-inflammatory and anti-allergic agent used clinically for the treatment of aphthous ulcers, allergic rhinitis, and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of IkB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1), suppresses a range of diseases or inflammatory conditions, such as obesity-related metabolic dysfunction and type 2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehensively studied. In this study, we investigated the novel therapeutic effect of amlexanox on LPS-induced neuroinflammation in vivo, and intraperitoneal injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as evidenced by ionized calcium-binding adapter molecule 1 (Iba1) immunostaining. Furthermore, amlexanox significantly reduced proinflammatory cytokines and chemokines in LPS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human HMC3 microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demonstrated that the anti-inflammatory action of amlexanox in BV2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In addition, the combination of amlexanox and SPI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a potential therapeutic strategy for neuroinflammation-related diseases.
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DOI: 10.1038/s41598-024-53235-5
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