Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat.
The current first line treatment of status epilepticus (SE) is based on the use of compounds that enhance GABAergic transmission or block sodium channels. These treatments discontinue SE in only two-thirds of patients, and therefore new therapeutic approaches are needed. We investigated whether a novel water-soluble AMPA antagonist, NS1209, discontinues SE in adult rats. SE was induced by electrical stimulation of the amygdala or subcutaneous administration of kainic acid. Animals were monitored continuously with video-electroencephalography during SE and drug treatment. We found that NS1209 could be safely administered to rats undergoing electrically induced SE at doses up to 50mg/kg followed by intravenous infusion of 5mg/kg for up to 24h. NS1209 administered as a bolus dose of 10-50mg/kg (i.p. or i.v.) followed by infusion of 4 or 5mg/kg h (i.v.) for 2-24h effectively discontinued electrically induced SE in all animals within 30-60 min, and there was no recurrence of SE after a 24-h infusion. Kainate-induced SE was similarly blocked by 10 or 30 mg/kg NS1209 (i.v.). To compare the efficacy and neuroprotective effects of NS1209 with those of diazepam (DZP), one group of rats received DZP (20mg/kg, i.p. and another dose of 10 mg/kg 6h later). By using the administration protocols described, the anticonvulsant effect of NS1209 was faster and more complete than that of DZP. NS1209 treatment (20 mg/kg bolus followed by 5mg/kg h infusion for 24 h) was neuroprotective against SE-induced hippocampal neurodegeneration, but to a lesser extent than DZP. These findings suggest that AMPA receptor blockade by NS1209 provides a novel and mechanistically complimentary addition to the armamentarium of drugs used to treat SE in humans.
Pitkänen
Asla
A
A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70 211 Kuopio, Finland. asla.pitkanen@uku.fi
Mathiesen
Claus
C
Rønn
Lars Christian B
LC
Møller
Arne
A
Nissinen
Jari
J
D000679:Amygdala / Q000473:pathology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000494:pharmacology; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000009:adverse effects; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects*; D007608:Kainic Acid; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013226:Status Epilepticus / Q000188:drug therapy* / Q000209:etiology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D014741:Video Recording
D000927:Anticonvulsants; D011758:Pyrroles; D018091:Receptors, AMPA; C119326:SPD 502; D044005:Tetrahydroisoquinolines; D003975:Diazepam; D007608:Kainic Acid