The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via σ 1 receptor activation

Comparison with the effects of dextromethorphan

Eun Joo Shin, Seung Yeol Nah, Won-Ki Kim, Kwang Ho Ko, Wang Kee Jhoo, Yong Kwang Lim, Joo Young Cha, Chieh Fu Chen, Hyoung Chun Kim

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at σ 1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10mgkg -1, i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24mgkg -1) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective σ 1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to σ 1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions.

Original languageEnglish
Pages (from-to)908-918
Number of pages11
JournalBritish Journal of Pharmacology
Volume144
Issue number7
DOIs
Publication statusPublished - 2005 Apr 1
Externally publishedYes

Fingerprint

Dextromethorphan
Kainic Acid
Seizures
Phencyclidine
Dextrorphan
Anticonvulsants
Transcription Factor AP-1
dimemorfan
Hippocampal CA3 Region
Hippocampal CA1 Region
Neuroprotective Agents

Keywords

  • σ Receptor
  • Anticonvulsants
  • AP-1 DNA-binding activity
  • Conditioned place preference
  • Dextromethorphan
  • Dimemorfan
  • Hippocampus
  • Kainate
  • Neuronal cell loss
  • Phencyclidine

ASJC Scopus subject areas

  • Pharmacology

Cite this

The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via σ 1 receptor activation : Comparison with the effects of dextromethorphan. / Shin, Eun Joo; Nah, Seung Yeol; Kim, Won-Ki; Ko, Kwang Ho; Jhoo, Wang Kee; Lim, Yong Kwang; Cha, Joo Young; Chen, Chieh Fu; Kim, Hyoung Chun.

In: British Journal of Pharmacology, Vol. 144, No. 7, 01.04.2005, p. 908-918.

Research output: Contribution to journalArticle

Shin, Eun Joo ; Nah, Seung Yeol ; Kim, Won-Ki ; Ko, Kwang Ho ; Jhoo, Wang Kee ; Lim, Yong Kwang ; Cha, Joo Young ; Chen, Chieh Fu ; Kim, Hyoung Chun. / The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via σ 1 receptor activation : Comparison with the effects of dextromethorphan. In: British Journal of Pharmacology. 2005 ; Vol. 144, No. 7. pp. 908-918.
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