Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats.
We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.
Shin
Eun-Joo
EJ
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
Nah
Seung-Yeol
SY
Chae
Jong Seok
JS
Bing
Guoying
G
Shin
Seung Woo
SW
Yen
Tran Phi Hoang
TP
Baek
In-Hyuk
IH
Kim
Won-Ki
WK
Maurice
Tangui
T
Nabeshima
Toshitaka
T
Kim
Hyoung-Chun
HC
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003915:Dextromethorphan / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology; D007150:Immunohistochemistry; D007859:Learning Disabilities / Q000139:chemically induced / Q000517:prevention & control / Q000523:psychology; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017478:Receptors, Phencyclidine / Q000187:drug effects; D017480:Receptors, sigma / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000523:psychology; D014298:Trimethyltin Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000097605:Sigma-1 Receptor
D000317:Adrenergic alpha-Antagonists; D003915:Dextromethorphan; D005029:Ethylenediamines; D010880:Piperidines; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D014298:Trimethyltin Compounds; D000097605:Sigma-1 Receptor; C046488:trimethyltin; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C010739:ifenprodil