Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3beta and NF-kappaB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection.
Article Details
- CitationCopy to clipboard
Chen CL, Cheng MH, Kuo CF, Cheng YL, Li MH, Chang CP, Wu JJ, Anderson R, Wang S, Tsai PJ, Liu CC, Lin YS
Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3beta and NF-kappaB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection.
Antimicrob Agents Chemother. 2018 May 25;62(6). pii: AAC.02045-17. doi: 10.1128/AAC.02045-17. Print 2018 Jun.
- PubMed ID
- 29581121 [ View in PubMed]
- Abstract
Group A Streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47(phox) and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3beta (GSK-3beta) activation, and subsequent NF-kappaB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3beta/NF-kappaB/NO signaling pathway.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dextromethorphan NADPH oxidase (Protein Group) Protein group Humans UnknownInhibitorDetails