The uremic guanidino compound guanidinosuccinic acid induces behavioral convulsions and concomitant epileptiform electrocorticographic discharges in mice.
As yet, the in vivo epileptogenic properties of guanidinosuccinic acid (GSA) remained highly conjectural, still requiring the demonstration of GSA-induced behavioral convulsions accompanied by epileptiform electrographic discharges. Therefore, Swiss mice were injected intraperitoneally (i.p.) with increasing doses of GSA. Full-blown clonic or clonic-tonic convulsions appeared in a dose-dependent manner, with a median latency of about 25 min. CD50 (convulsive dose of the drug in 50% of the animals), the LD50 (lethal dose in 50%), and their 95% confidence limits for GSA suspensions in i.p. administration were 363 (287-458) mg/kg and 579 (445-756) mg/kg, respectively. In addition, four-channel electrocorticographic (ECoG) recordings were made in freely moving mice following the injection of 700 mg/kg (CD97). Epileptiform ECoG discharges coincided with the behavioral manifestation of the GSA-induced convulsions starting with initial decrease in amplitude, occasional spike-waves (10-20 min after injection), eventually leading to sustained spiking and spike-wave activity (30-50 min after injection). Clonic convulsions induced by a CD97 dose of GSA were only moderately attenuated by high doses of i.p. phenobarbital (20, 40 and 80 mg/kg), while tonic extension and lethal effects were dose-dependently blocked. A dose of 1000 mg/kg (CD97 for tonic extension) induced tonic extension in 100% of the animals, following treatment with 20 mg/kg of phenytoin none of the animals displayed tonic extension, and following 10 mg/kg only 30% of the animals displayed tonic extension, while the occurrence of clonic convulsions was not significantly attenuated.
D'Hooge
R
R
Laboratory of Neurochemistry and Behavior, Born-Bunge Foundation, University of Antwerp (UIA), Belgium.
Pei
Y Q
YQ
Manil
J
J
De Deyn
P P
PP
D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D004569:Electroencephalography / Q000187:drug effects*; D004827:Epilepsy / Q000139:chemically induced*; D005260:Female; D006146:Guanidines / Q000633:toxicity*; D008297:Male; D051379:Mice; D013386:Succinates / Q000633:toxicity*; D014511:Uremia / Q000378:metabolism*
D003292:Convulsants; D006146:Guanidines; D013386:Succinates; C001318:guanidinosuccinic acid