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

doi:10.1016/S0024-3205(02)02309-3

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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 language	English
Pages (from-to)	769-783
Number of pages	15
Journal	Life Sciences
Volume	72
Issue number	7
DOIs	https://doi.org/10.1016/S0024-3205(02)02309-3
State	Published - Jan 3 2003

Bibliographical note

Funding Information:
We thank Drs. J.S. Hong and M.J. Iadarola for donating antiserum against FRA. This study was supported by a grant of the Biomedical Brain Research Center Grant (01-PJ8-PG6-01NE01-0003), Ministry of Health and Welfare, Republic of Korea. Equipment at the Institute of Pharmaceutical Science (Kangwon National University) was used for this study.

Keywords

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

ASJC Scopus subject areas

General Pharmacology, Toxicology and Pharmaceutics
General Biochemistry, Genetics and Molecular Biology

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10.1016/S0024-3205(02)02309-3

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

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.",

keywords = "AP-1 DNA binding activity, Fos-related antigen immunoreactivity, Hippocampus, Morphinans, Mouse, σ-1 receptor",

author = "Kim, {Hyoung Chun} and Guoying Bing and Jhoo, {Wang Kee} and Kim, {Won Ki} and Shin, {Eun Joo} and Im, {Doo Hyun} and Kang, {Kee Seok} and Ko, {Kwang Ho}",

note = "Funding Information: We thank Drs. J.S. Hong and M.J. Iadarola for donating antiserum against FRA. This study was supported by a grant of the Biomedical Brain Research Center Grant (01-PJ8-PG6-01NE01-0003), Ministry of Health and Welfare, Republic of Korea. Equipment at the Institute of Pharmaceutical Science (Kangwon National University) was used for this study.",

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AU - Kim, Hyoung Chun

AU - Bing, Guoying

AU - Jhoo, Wang Kee

AU - Kim, Won Ki

AU - Shin, Eun Joo

AU - Im, Doo Hyun

AU - Kang, Kee Seok

AU - Ko, Kwang Ho

N1 - Funding Information: We thank Drs. J.S. Hong and M.J. Iadarola for donating antiserum against FRA. This study was supported by a grant of the Biomedical Brain Research Center Grant (01-PJ8-PG6-01NE01-0003), Ministry of Health and Welfare, Republic of Korea. Equipment at the Institute of Pharmaceutical Science (Kangwon National University) was used for this study.

PY - 2003/1/3

Y1 - 2003/1/3

N2 - 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.

AB - 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.

KW - AP-1 DNA binding activity

KW - Fos-related antigen immunoreactivity

KW - Hippocampus

KW - Morphinans

KW - Mouse

KW - σ-1 receptor

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AN - SCOPUS:0037414671

SN - 0024-3205

VL - 72

SP - 769

EP - 783

JO - Life Sciences

JF - Life Sciences

IS - 7

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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