Quinolinic acid promotes seizures and decreases glutamate uptake in young rats: reversal by orally administered guanosine.
Quinolinic acid (QA) has been used as a model for experimental overstimulation of the glutamatergic system. Glutamate uptake is the main mechanism involved in the maintenance of extracellular glutamate below toxic levels. Guanosine systemically administered prevents quinolinic acid-induced seizures in adult mice and increases basal glutamate uptake by cortical astrocyte culture and slices from young rats. The immature brain differs from the adult brain in its susceptibility to seizures, seizure characteristics, and responses to antiepileptic drugs (AED). Here we investigated the effect of guanosine p.o. on QA-induced seizures in young rats (P12-14) and upon ex vivo glutamate uptake by cortical slices from these animals. I.c.v. infusion of 250 nmol QA induced seizures in all animals and decreased glutamate uptake. I.p. injection of MK-801 and phenobarbital 30 min before QA administration prevented seizures in all animals. Guanosine (7.5 mg/kg) 75 min before QA prevented seizures in 50% of animals as well as prevented the decrease of glutamate uptake in the protected animals. To investigate if the anticonvulsive effect of guanosine was specific for QA-induced seizures, the picrotoxin-induced seizures model was also performed. Pretreatment with phenobarbital i.p. (60 mg/kg-30 min) prevented picrotoxin-induced seizures in all animals, whereas guanosine p.o. (7.5 mg/kg-75 min) and MK-801 i.p. (0.5 mg/kg-30 min) had no effect. Thus, guanosine protection on the QA-induced seizures in young rats and on the decrease of glutamate uptake showed some specificity degree towards the QA-induced toxicity. This points that guanosine could be considered for treatments of epilepsy, and possibly other neurological disorders in children.
de Oliveira
Diogo Losch
DL
Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, 90.035.003 Brazil.
Horn
Joel Felipe
JF
Rodrigues
Juliana Moura
JM
Frizzo
Marcos E S
ME
Moriguchi
Emílio
E
Souza
Diogo Onofre
DO
Wofchuk
Susana
S
D000284:Administration, Oral; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D006151:Guanosine / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010852:Picrotoxin; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D006151:Guanosine; D010634:Phenobarbital; D010852:Picrotoxin; D017378:Quinolinic Acid