Effects of some excitatory amino acid antagonists on imipenem-induced seizures in DBA/2 mice.
The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (+/-)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((+/-)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) > 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 > Msc > (-)-2-amino-7-phosphonic acid (AP7) > gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABAA agonist, was able to protect against seizures induced by Imi.
De Sarro
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G
Department of Experimental and Clinical Medicine, School of Medicine, University of Reggio Calabria, Cantanzaro, Italy.
Ammendola
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D
Nava
F
F
De Sarro
A
A
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000037:antagonists & inhibitors*; D005973:Glutamine / Q000031:analogs & derivatives / Q000494:pharmacology; D015378:Imipenem / Q000009:adverse effects*; D007736:Kynurenic Acid / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D009118:Muscimol / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced*
D000596:Amino Acids; D000927:Anticonvulsants; D018846:Excitatory Amino Acids; D010879:Piperazines; D010880:Piperidines; D011810:Quinoxalines; D005973:Glutamine; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C064540:CGP 39551; C065286:SDZ EAA 494; D009118:Muscimol; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015378:Imipenem; D015763:2-Amino-5-phosphonovalerate; C042626:gamma-glutamylaminomethylsulfonic acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007736:Kynurenic Acid; C031231:2-amino-7-phosphonoheptanoic acid; C010739:ifenprodil