Anticonvulsant effect of GMP depends on its conversion to guanosine.
Studies on the purinergic system normally deal with adenine-based purines, namely, adenine nucleotides and adenosine. However, a guanine-based purinergic system may also have important neuromodulatory roles. Guanine-based purines exert trophic effects on neural cells, protect brain slices in a model of hypoxia and stimulate glutamate uptake. In vivo, both guanosine 5'-monophosphate (GMP) and guanosine (GUO) protected against seizures. In this study, we investigated if the anticonvulsant effect of GMP is mediated by guanosine and if guanosine or GMP treatments were able to increase adenosine levels. Intraperitoneal (i.p.) treatments with 7.5 mg/kg GMP or guanosine prevented 50% of seizures by quinolinic acid (QA) and increased guanosine cerebrospinal fluid (CSF) levels around twofold and threefold, respectively; GMP and adenosine levels remained unchanged. Intracerebroventricular treatment with 960 nmol GMP prevented 80% of seizures and the 5'-nucleotidase inhibitor alpha-beta-methyleneadenosine 5'-diphosphate (AOPCP), when injected 3 min before, reduced this anticonvulsant effect to 30% protection as well as significantly decreased the conversion of GMP into guanosine measured in the CSF. This study shows that the previously reported effect of GMP as an anticonvulsant seems to be related to its ability to generate guanosine through the action of ecto-5'-nucleotidase.
Soares
Félix A
FA
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 Anexo CEP 90.035-003, Porto Alegre, RS, Brazil.
Schmidt
André P
AP
Farina
Marcelo
M
Frizzo
Marcos E S
ME
Tavares
Rejane G
RG
Portela
Luís V C
LV
Lara
Diogo R
DR
Souza
Diogo O
DO
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006151:Guanosine / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000134:cerebrospinal fluid / Q000188:drug therapy*
D000927:Anticonvulsants; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D006151:Guanosine; D000244:Adenosine Diphosphate; D006152:Cyclic GMP