The effects of dextromethorphan on kainic acid-induced seizures in the rat.
Several studies have shown that dextromethorphan (DM) has both anticonvulsant and proconvulsant effects depending on the animal model. In this study, we examined the effects of DM on three parameters associated with kainic acid (KA)-induced seizures: cell loss in the hippocampus, increased AP-1 DNA binding activity and increased c-Jun and fos-related antigen (FRA) expression. KA administration (8 mg/kg, ip) produced robust behavioral convulsions lasting 4-6 hr. Pretreatment with DM (12.5-75 mg/kg, po) 15 min before KA injections reduced the seizures as well as mortality in a dose-dependent manner. Histological studies revealed a severe loss of cells in the CA1 and CA3 fields of the hippocampus in KA-treated rats. DM pretreatment also reduced this cell loss in a dose-dependent fashion. Biochemical studies showed that DM pretreatment also attenuated the KA-induced increase of AP-1 binding activity and c-Jun/FRA expression in the hippocampus. These results indicate that DM is an effective antagonist of KA.
Kim
H C
HC
Section of Neuropharmacology, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, North Carolina 27709, USA.
Pennypacker
K R
KR
Bing
G
G
Bronstein
D
D
McMillian
M K
MK
Hong
J S
JS
D000818:Animals; D015153:Blotting, Western; D003915:Dextromethorphan / Q000627:therapeutic use*; D018690:Excitatory Amino Acid Agonists; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D003915:Dextromethorphan; D007608:Kainic Acid