guanidinosuccinic-acid and Epilepsy

Guanidinosuccinic acid (GSA) is a guanidino compound found in mammalian central nervous system and physiological fluids. Its level has been found to be greatly increased in serum and cerebrospinal fluid of patients with renal failure, and the compound is suggested to play a role in uremic encephalopathy. In this report we examined the behavioral, electrographic and morphological effects of intrahippocampal GSA injection in unanesthetized rats. Intrahippocampal administration of 2 microliters GSA solution (3.5 nM) was followed by behavior observation, and electrohippocampographic and electrocorticographic recording. GSA-injected animals showed partial clonic seizures leading to generalized clonic seizures, and eventually status epilepticus. These were accompanied by epileptiform electrographic discharges. During generalized clonic seizures, the electrohippocampogram showed arythmic bursting spikes. Epileptiform electric activity persisted even after the generalized clonic convulsions had stopped, and lasted until the animals were killed, 5 days following injection. Microscopic examination of brain slices of these rats revealed severe neural damage in CA1 area of hippocampus. Treatment of rats with the non-competitive NMDA receptor antagonist ketamine prevented both partial and generalized clonic seizures, epileptiform electrographic discharges, and GSA-induced hippocampal damage.

Topics: Animals; Epilepsy; Female; Guanidines; Hippocampus; Injections, Spinal; Male; Rats; Rats, Wistar; Succinates

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.

Topics: Animals; Convulsants; Electroencephalography; Epilepsy; Female; Guanidines; Male; Mice; Succinates; Uremia