Oxycodone alleviates LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis

• Published in: Journal of toxicological sciences Vol. 49; no. 10; pp. 435 - 446
• Main Authors: Tan, QingYun, Zhang, Kai, Wang, QingDong, Zang, Rongjia
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2024; Japan Science and Technology Agency
• Subjects: 3' Untranslated regions; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Assaying; Binding; Cell Line; Cell viability; CREB; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Enzyme-linked immunosorbent assay; Humans; Inflammation - chemically induced; Inflammation - genetics; Interleukins; Lipopolysaccharides; Microglia; Microglia - drug effects; Microglia - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; miR-181c; mRNA; neuroinflammation; Neuroinflammatory Diseases - chemically induced; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - genetics; Neurological diseases; Nitric-oxide synthase; Oxycodone; Oxycodone - adverse effects; Oxycodone - pharmacology; PDCD4; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction - drug effects; Tumor necrosis factor-α; Western blotting; PDCD4; CREB; neuroinflammation; miR-181c; Oxycodone
• ISSN: 0388-1350; 1880-3989; 1880-3989
• DOI: 10.2131/jts.49.435

Background: Neuroinflammation plays a critical role in various neurological disorders. Oxycodone has anti-inflammatory properties. The purpose of this work was to look into the effect of oxycodone in controlling lipopolysaccharide (LPS)-induced neuroinflammation in microglia. Methods: LPS-induced HMC3 cells were subjected to oxycodone (2.5, 5, 10 and 20 μg/mL). The mRNA and protein expressions were examined by qRT-PCR and western blotting. TNF-α, IL-1β, IL-6, and IL-8 levels were assessed by ELISA. MTT assay was adopted to measure cell viability. The interactions between CREB, miR-181c and PDCD4 were analyzed by dual-luciferase reporter assay, ChIP and/or RIP assays. Results: Oxycodone treatment alleviated LPS-induced inflammation in HMC3 cells and increased p-CREB level, but reduced PDCD4 and iNOS levels in LPS-treated cells. Mechanistically, oxycodone mitigated LPS-induced neuroinflammation by upregulating miR-181c. In addition, CREB promoted miR-181c expression by directly binding to the MIR181C promoter, and miR-181c inhibited PDCD4 expression by directly binding to PDCD4 3’UTR. As expected, oxycodone alleviated LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis. Conclusion: Oxycodone attenuated LPS-induced neuroinflammation in microglia by regulating the CREB/miR-181c/PDCD4 axis. These findings proved that oxycodone is a potential drug for treating neuroinflammation and elucidate the mechanisms involved.