title: An antagonist of calcium permeable AMPA receptors, IEM1460: Anticonvulsant action in immature rats?
abstract: AMPA receptors lacking GluA2 subunit are widely distributed in developing brain. IEM1460 as a specific antagonist of these receptors might be a potential age-specific anticonvulsant. Possible anticonvulsant action was assessed in two models of epileptic seizures: pentylenetetrazol (PTZ) - induced convulsions and cortical afterdischarges elicited in 12-, 18- and 25-day-old rats. IEM1460 was administered intraperitoneally in doses of 3, 10 and 20mg/kg. Pretreatment with IEM1460 at the dose of 20mg/kg resulted in delayed onset of PTZ-induced minimal clonic seizures in all age groups. PTZ-induced generalized tonic-clonic seizures were suppressed in 18- and 25-day-old rats by 10 and 20mg/kg doses of IEM1460. Duration of cortical afterdischarges progressively increased with repeated stimulations in control 12-day-old rats. The IEM1460 dose of 10mg/kg fully blocked this prolongation and the 20-mg/kg dose partly suppressed it. Administration of IEM1460 had moderate proconvulsant effect on 18- and 25-day-old animals - afterdischarges were prolonged with repeated stimulations. The duration of cortical epileptic afterdischarges in adult (80-day-old) animals was not affected by IEM1460. Effects of IEM1460 are dependent on the model of seizures used, their ictogenic structures and developmental changes in subunit composition of AMPA receptors.
authors.affiliation: Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic. Electronic address: ewa.szczurowska@epilepsy.biomed.cas.cz.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szczurowska
authors.affiliation: Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Mareš
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography; D008297:Male; D010433:Pentylenetetrazole; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology*
chemical_list: D000927:Anticonvulsants; C110702:IEM 1460; D018091:Receptors, AMPA; D000218:Adamantane; D010433:Pentylenetetrazole
keywords: AMPA receptors; Cortical afterdischarges; IEM1460; Immature rats; Pentetrazol