The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan.
In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 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 (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-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 sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 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.
Shin
Eun-Joo
EJ
Neurotoxicology Program, College of Pharmacy, Korea Institute of Drug Abuse, Kangwon National University, Chunchon 200-701, South Korea.
Nah
Seung-Yeol
SY
Kim
Won-Ki
WK
Ko
Kwang Ho
KH
Jhoo
Wang-Kee
WK
Lim
Yong-Kwang
YK
Cha
Joo Young
JY
Chen
Chieh-Fu
CF
Kim
Hyoung-Chun
HC
D000818:Animals; D003915:Dextromethorphan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism
D009019:Morphinans; D017480:Receptors, sigma; C101491:sigma1-binding protein, rat; C012621:dimemorfan; D003915:Dextromethorphan; D007608:Kainic Acid
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