Dextromethorphan attenuates NADPH oxidase-regulated glycogen synthase kinase 3 and NF-B activation and reduces nitric oxide production in group a streptococcal infection

Chia-Ling Chen, Miao-Huei Cheng, Chih-Feng Kuo, Yi-Lin Cheng, Ming-Han Li, Chih-Peng Chang, Jiunn-Jong Wu, Robert Anderson, Shuying Wang, Pei-Jane Tsai, Ching-Chuan Liu, Yee-Shin Lin

Research output: Contribution to journalArticle

5 Citations (Scopus)

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-3 (GSK-3) activation, and subsequent NF-B 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-3/NF-B/NO signaling pathway.

Original languageEnglish
Article numbere02045-17
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number6
Early online dateMar 26 2018
DOIs
Publication statusPublished - Jun 1 2018

Keywords

  • Dextromethorphan
  • Group A Streptococcus
  • Inflammation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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