Protective effect of dextromethorphan against endotoxic shock in mice

Guorong Li, Yuxin Liu, Nian Ssheng Tzeng, Gang Cui, Michelle Block, Belinda Wilson, Liya Qin, Tongguang Wang, Bin Liu, Jie Liu, Jau Shyong Hong

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/D-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 h after an injection of LPS/GalN (20 μg/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-α) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-α clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis.

Original languageEnglish (US)
Pages (from-to)233-240
Number of pages8
JournalBiochemical Pharmacology
Volume69
Issue number2
DOIs
StatePublished - Jan 15 2005
Externally publishedYes

Fingerprint

Dextromethorphan
Septic Shock
Galactosamine
Lipopolysaccharides
Cell death
Superoxides
Injections
Morphinans
Cell Death
Tumor Necrosis Factor-alpha
Genes
Transcription Factor CHOP
Chemokine CXCL2
Antitussive Agents
Inflammation
Thrombospondin 1
CXC Chemokines
Kupffer Cells
Microglia
Neuroprotective Agents

Keywords

  • DM
  • Gene expression
  • Inflammation
  • Liver injury
  • LPS/Ga1N
  • ROS

ASJC Scopus subject areas

  • Pharmacology

Cite this

Protective effect of dextromethorphan against endotoxic shock in mice. / Li, Guorong; Liu, Yuxin; Tzeng, Nian Ssheng; Cui, Gang; Block, Michelle; Wilson, Belinda; Qin, Liya; Wang, Tongguang; Liu, Bin; Liu, Jie; Hong, Jau Shyong.

In: Biochemical Pharmacology, Vol. 69, No. 2, 15.01.2005, p. 233-240.

Research output: Contribution to journalArticle

Li, G, Liu, Y, Tzeng, NS, Cui, G, Block, M, Wilson, B, Qin, L, Wang, T, Liu, B, Liu, J & Hong, JS 2005, 'Protective effect of dextromethorphan against endotoxic shock in mice', Biochemical Pharmacology, vol. 69, no. 2, pp. 233-240. https://doi.org/10.1016/j.bcp.2004.10.003
Li, Guorong ; Liu, Yuxin ; Tzeng, Nian Ssheng ; Cui, Gang ; Block, Michelle ; Wilson, Belinda ; Qin, Liya ; Wang, Tongguang ; Liu, Bin ; Liu, Jie ; Hong, Jau Shyong. / Protective effect of dextromethorphan against endotoxic shock in mice. In: Biochemical Pharmacology. 2005 ; Vol. 69, No. 2. pp. 233-240.
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AU - Wilson, Belinda

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