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Protective effect of dextromethorphan against endotoxic shock in mice
- Source :
-
Biochemical Pharmacology . Jan2005, Vol. 69 Issue 2, p233-240. 8p. - Publication Year :
- 2005
-
Abstract
- 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 (12.5mg/kg, s.c.) 30min before and 2, 4h after an injection of LPS/GalN (20μg/700mg/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 30min 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. [Copyright &y& Elsevier]
- Subjects :
- *ENDOTOXINS
*HEPATOTOXICOLOGY
*AMINOTRANSFERASES
*KUPFFER cells
Subjects
Details
- Language :
- English
- ISSN :
- 00062952
- Volume :
- 69
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Biochemical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17205488
- Full Text :
- https://doi.org/10.1016/j.bcp.2004.10.003