RESUMO
Intraperitoneal guanosine has been shown to prevent quinolinic acid-induced seizures in mice. In this study, we investigated the effect of orally administered guanosine on seizures induced by the glutamate agonists quinolinic acid and kainate, and the endogenous glutamate releaser alpha-dendrotoxin. Guanosine (7.5 mg/kg, per os), administered 75 min in advance, prevented 70% of seizures induced by i.c.v. quinolinic acid, being as efficient as the NMDA channel blocker MK-801 administered intraperitoneally. Guanosine was ineffective against kainate-induced seizures, but significantly reversed the potentiation of seizures and death caused by the concomitant injection of MK-801. Guanosine also significantly prevented seizures and death induced by i.c.v. alpha-dendrotoxin, whereas MK-801 and phenobarbital only prevented death. Altogether, our findings underscore the therapeutic potential of oral administration of guanosine for treating diseases involving glutamatergic excitotoxicity, including epilepsy.
Assuntos
Encéfalo/efeitos dos fármacos , Morte , Epilepsia/tratamento farmacológico , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Guanosina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cafeína/farmacologia , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Venenos Elapídicos/farmacologia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , Masculino , Camundongos , Fenobarbital/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Ácido Quinolínico/farmacologia , Receptores Purinérgicos P1/efeitos dos fármacos , Receptores Purinérgicos P1/metabolismoRESUMO
Chick kainate binding protein was solubilized from cerebellar membranes and purified (x19) by use of two chromatographic steps. Measurements of [3H]kainate binding and GTPase activity in the different fractions reveal a consistent decrease of GTPase activity as the purification proceeds so that no GTPase is detectable after the final purification step. This fact, in the context of the differential involvement in nucleotide recognition of some critical amino acid residues in the p-loop motif of GTPases and in the guanine nucleotide-binding sequence of ionotropic glutamate receptors, together with significant discrepancies concerning the activity of individual nucleotides, suggests that both guanine nucleotide-recognizing sequences are unlikely to be alternative expressions of the same functional domain.