Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice.
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 microg/0.5 microl) pretreatment significantly attenuated seizures induced by kainic acid (0.07 microg/0.07 microl) 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 sigma-1 site, we examined the role of the sigma-1 receptor on the pharmacological action mediated by DM or DX. Pretreatment with the sigma-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 sigma-1 receptor modulation.
Kim
Hyoung-Chun
HC
Neurotoxicology Program, Department of Pharmacy, College of Pharmacy, Korea Institute of Drug Abuse, Kangwon National University, Chunchon 200-701, South Korea. kimhc@cc.kangwon.ac.kr
Bing
Guoying
G
Jhoo
Wang-Kee
WK
Kim
Won-Ki
WK
Shin
Eun-Joo
EJ
Im
Doo-Hyun
DH
Kang
Kee-Seok
KS
Ko
Kwang-Ho
KH
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D004247:DNA / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D003917:Dextrorphan / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016760:Proto-Oncogene Proteins c-fos; D017465:Receptors, Opioid, delta; D018808:Transcription Factor AP-1; D003917:Dextrorphan; D003915:Dextromethorphan; D004247:DNA; D007608:Kainic Acid