Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice

Hyoung Chun Kim, Guoying Bing, Wang Kee Jhoo, Won Ki Kim, Eun Joo Shin, Doo Hyun Im, Kee Seok Kang, Kwang Ho Ko

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The effects of dextromethorphan (DM), and its major metabolite dextrorphan (DX) on kainic acid-induced seizures in mice were examined. Intracerebroventricular DM or DX (5 or 10 μg/0.5μl) pretreatment significantly attenuated seizures induced by kainic acid (0.07 μg/0.07 μl) in a dose-related manner. DM or DX pretreatment significantly attenuated kainic acid-induced increases in AP-1 DNA-binding activity and fos-related antigen-immunoreactivity as well as neuronal loss in the hippocampus. DM appears to be a more potent neuroprotectant than DX. Since the high-affinity DM binding sites are recognized as being identical to the σ-1 site, we examined the role of the σ-1 receptor on the pharmacological action mediated by DM or DX. Pretreatment with the σ-1 receptor antagonist BD1047 (2.5 or 5 mg/kg, i.p.) blocked the neuroprotection by DM in a dose-related manner. This effect of BD 1047 was more pronounced in the animals treated with DM than in those treated with DX. Combined, our results suggest that metabolism of DM to DX is not essential for DM to exert its effect. They also suggest that DM provides neuroprotection from kainic acid via σ-1 receptor modulation.

Original languageEnglish
Pages (from-to)769-783
Number of pages15
JournalLife Sciences
Volume72
Issue number7
DOIs
Publication statusPublished - 2003 Jan 3
Externally publishedYes

Keywords

  • AP-1 DNA binding activity
  • Fos-related antigen immunoreactivity
  • Hippocampus
  • Morphinans
  • Mouse
  • σ-1 receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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