Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice.
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 Ca2+ 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 (37.5 microg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5 mg/kg), dimemorfan (6.25 or 12.5 mg/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.
Shin
Eun-Joo
EJ
Neurotoxicology Program, College of Pharmacy, Korea Institute of Drug Abuse, Chunchon 200-701, South Korea.
Nabeshima
Toshitaka
T
Lee
Phil Ho
PH
Kim
Won-Ki
WK
Ko
Kwang Ho
KH
Jhoo
Jin-Hyeong
JH
Jhoo
Wang-Kee
WK
Cha
Joo Young
JY
Kim
Hyoung-Chun
HC
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D003720:Densitometry / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000302:isolation & purification / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D000927:Anticonvulsants; D020746:Calcium Channels, L-Type; D009019:Morphinans; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C012621:dimemorfan; D012313:RNA; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D010622:Phencyclidine