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

Hyoung Chun Kim, Guoying Bing, Wang K. Jhoo, Won-Ki Kim, Eun J. Shin, Doo Hyun Im, Kee Seok Kang, Kwang H. Ko

Research output: Contribution to journalArticle

33 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

Fingerprint

Dextrorphan
Dextromethorphan
Kainic Acid
Metabolism
Anticonvulsants
Seizures
Proto-Oncogene Proteins c-fos
Transcription Factor AP-1
Neuroprotective Agents
Metabolites
Hippocampus

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice. / Kim, Hyoung Chun; Bing, Guoying; Jhoo, Wang K.; Kim, Won-Ki; Shin, Eun J.; Im, Doo Hyun; Kang, Kee Seok; Ko, Kwang H.

In: Life Sciences, Vol. 72, No. 7, 03.01.2003, p. 769-783.

Research output: Contribution to journalArticle

Kim, Hyoung Chun ; Bing, Guoying ; Jhoo, Wang K. ; Kim, Won-Ki ; Shin, Eun J. ; Im, Doo Hyun ; Kang, Kee Seok ; Ko, Kwang H. / Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice. In: Life Sciences. 2003 ; Vol. 72, No. 7. pp. 769-783.
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