title: Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats.
abstract: The Na⁺/Ca²⁺ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic-clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, and 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic-clonic components in 12-62% and 25-62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, and 30 mg/kg; p.o.), clonic and tonic-clonic PTZ-induced generalized seizures were reduced in 25-50% and 38-63% of treated animals, respectively. SN-6 (0.3, 1, and 3 mg/kg; p.o.) also significantly reduced PTZ-induced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3 and 30 mg/kg; p.o.) or SN-6 (3 and 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic-clonic PTZ-induced seizures. These findings suggested that Ca²⁺ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic-clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.
authors.affiliation: Department of Pediatrics, Bldg. D, Room 285, Georgetown University Medical Center, 3900 Reservoir Rd, NW, Washington, DC 20057, USA. pn@georgetown.edu
authors.forename: Prosper
authors.initials: P
authors.lastname: N'Gouemo
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D001593:Benzyl Compounds / Q000627:therapeutic use; D016009:Chi-Square Distribution; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D008297:Male; D010433:Pentylenetetrazole / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053778:Thiazolidines / Q000627:therapeutic use; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D000927:Anticonvulsants; D001593:Benzyl Compounds; D003292:Convulsants; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines; D013890:Thiourea; D010433:Pentylenetetrazole