Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice

Eun Joo Shin, Toshitaka Nabeshima, Phil Ho Lee, Won-Ki Kim, Kwang Ho Ko, Jin Hyeong Jhoo, Wang Kee Jhoo, Joo Young Cha, Hyoung Chun Kim

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.

Original languageEnglish
Pages (from-to)267-276
Number of pages10
JournalBehavioural Brain Research
Volume151
Issue number1-2
DOIs
Publication statusPublished - 2004 May 5
Externally publishedYes

Fingerprint

Calcium Channel Agonists
L-Type Calcium Channels
Dextromethorphan
Seizures
Dextrorphan
Morphinans
Molecular Mechanisms of Pharmacological Action
Proto-Oncogene Proteins c-fos
Convulsants
Phencyclidine
Electroshock
dimemorfan
Transcription Factor AP-1
Calcium Channels
Locomotion
Anticonvulsants
Injections

Keywords

  • AP-1 DNA binding activity
  • BAY k-8644
  • c-fos
  • c-jun
  • Dextromethorphan
  • Dimemorfan
  • fos-related antigen
  • Phencyclidine-like behavior

ASJC Scopus subject areas

  • Behavioral Neuroscience

Cite this

Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice. / Shin, Eun Joo; Nabeshima, Toshitaka; Lee, Phil Ho; Kim, Won-Ki; Ko, Kwang Ho; Jhoo, Jin Hyeong; Jhoo, Wang Kee; Cha, Joo Young; Kim, Hyoung Chun.

In: Behavioural Brain Research, Vol. 151, No. 1-2, 05.05.2004, p. 267-276.

Research output: Contribution to journalArticle

Shin, EJ, Nabeshima, T, Lee, PH, Kim, W-K, Ko, KH, Jhoo, JH, Jhoo, WK, Cha, JY & Kim, HC 2004, 'Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice', Behavioural Brain Research, vol. 151, no. 1-2, pp. 267-276. https://doi.org/10.1016/j.bbr.2003.09.004
Shin, Eun Joo ; Nabeshima, Toshitaka ; Lee, Phil Ho ; Kim, Won-Ki ; Ko, Kwang Ho ; Jhoo, Jin Hyeong ; Jhoo, Wang Kee ; Cha, Joo Young ; Kim, Hyoung Chun. / Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice. In: Behavioural Brain Research. 2004 ; Vol. 151, No. 1-2. pp. 267-276.
@article{5ce1e4e0b7bb4679bc956de573bc6087,
title = "Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice",
abstract = "A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.",
keywords = "AP-1 DNA binding activity, BAY k-8644, c-fos, c-jun, Dextromethorphan, Dimemorfan, fos-related antigen, Phencyclidine-like behavior",
author = "Shin, {Eun Joo} and Toshitaka Nabeshima and Lee, {Phil Ho} and Won-Ki Kim and Ko, {Kwang Ho} and Jhoo, {Jin Hyeong} and Jhoo, {Wang Kee} and Cha, {Joo Young} and Kim, {Hyoung Chun}",
year = "2004",
month = "5",
day = "5",
doi = "10.1016/j.bbr.2003.09.004",
language = "English",
volume = "151",
pages = "267--276",
journal = "Behavioural Brain Research",
issn = "0166-4328",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice

AU - Shin, Eun Joo

AU - Nabeshima, Toshitaka

AU - Lee, Phil Ho

AU - Kim, Won-Ki

AU - Ko, Kwang Ho

AU - Jhoo, Jin Hyeong

AU - Jhoo, Wang Kee

AU - Cha, Joo Young

AU - Kim, Hyoung Chun

PY - 2004/5/5

Y1 - 2004/5/5

N2 - A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.

AB - A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.

KW - AP-1 DNA binding activity

KW - BAY k-8644

KW - c-fos

KW - c-jun

KW - Dextromethorphan

KW - Dimemorfan

KW - fos-related antigen

KW - Phencyclidine-like behavior

UR - http://www.scopus.com/inward/record.url?scp=16544393829&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16544393829&partnerID=8YFLogxK

U2 - 10.1016/j.bbr.2003.09.004

DO - 10.1016/j.bbr.2003.09.004

M3 - Article

C2 - 15084442

AN - SCOPUS:16544393829

VL - 151

SP - 267

EP - 276

JO - Behavioural Brain Research

JF - Behavioural Brain Research

SN - 0166-4328

IS - 1-2

ER -