Guanosine and GMP prevent seizures induced by quinolinic acid in mice.
In the mammalian CNS, glutamate and GABA are the principal neurotransmitters mediating excitatory and inhibitory synaptic events, respectively, and have been implicated in the neurobiology of seizures. Guanine-based purines, including the nucleoside guanosine and the nucleotide GMP, have been shown to antagonize glutamatergic activity at the receptor level and the other purine nucleoside adenosine is a well-known modulator of seizure threshold. In the present study we investigated the anticonvulsant effect of i. p. guanosine and GMP against seizures induced by the glutamate agonist quinolinic acid (QA) or the GABA(A) antagonist picrotoxin in mice. Animals were pretreated with an i.p. injection of saline, guanosine or GMP 30 min before either an i.c.v. injection of 4 microliter QA (36.8 nmol) or a subcutaneous injection of picrotoxin (3.2 mg/kg). All animals pretreated with vehicle followed by QA or picrotoxin presented seizures, which were completely prevented by the NMDA antagonist MK-801 and the GABA agonist phenobarbital, respectively. Guanosine and GMP dose-dependently protected against QA-induced seizures, up to 70 and 80% at 7.5 mg/kg, with ED(50)=2. 6+/-0.4 and 1.7+/-0.6 mg/kg, respectively. Conversely, neither guanosine, GMP nor MK-801 affected picrotoxin-induced seizures, indicating some degree of specificity towards the glutamatergic system. This study suggests anticonvulsant properties of i.p. guanosine and GMP, which may be related with antagonism of glutamate receptors.
Schmidt
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AP
Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Avenida Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, Brazil. aschmidt@vortex.ufrgs.br
Lara
D R
DR
de Faria Maraschin
J
J
da Silveira Perla
A
A
Onofre Souza
D
D
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology*; D004827:Epilepsy / Q000209:etiology / Q000503:physiopathology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid / Q000378:metabolism; D006151:Guanosine / Q000378:metabolism* / Q000494:pharmacology*; D006157:Guanosine Monophosphate / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010852:Picrotoxin / Q000494:pharmacology; D017378:Quinolinic Acid / Q000378:metabolism* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid; D006151:Guanosine; D006157:Guanosine Monophosphate; D010852:Picrotoxin; D017378:Quinolinic Acid; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1; D005680:gamma-Aminobutyric Acid