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Effects of some excitatory amino acid antagonists on imipenem-induced seizures in DBA/2 mice
G De Sarro1, D Ammendola, F Nava
1Department of Experimental and Clinical Medicine, School of Medicine, University of Reggio Calabria, Cantanzaro, Italy.
Abstract:
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.
Insights
Imipenem (Imi) can induce seizures in mice through complex mechanisms involving excitatory amino acids and GABA neurotransmission. Anticonvulsant drugs targeting these systems, like MK-801 and muscimol, show protective effects against imipenem-induced seizures.
Area of Science:
- Neuropharmacology
- Epilepsy Research
- Carbapenem Antibiotics
Background:
- Imipenem (Imi), a carbapenem antibiotic, is known to cause central nervous system side effects, including seizures.
- DBA/2 mice are genetically susceptible to sound-induced seizures, making them a relevant model for studying seizure mechanisms.
- Understanding the neurochemical basis of imipenem-induced seizures is crucial for patient safety and developing therapeutic interventions.
Purpose of the Study:
- To investigate the behavioral and convulsant effects of imipenem (Imi) following intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration in DBA/2 mice.
- To evaluate the anticonvulsant potential of various excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against imipenem-induced seizures.
- To elucidate the potential mechanisms underlying imipenem-induced seizures, focusing on interactions with excitatory amino acid and GABAergic systems.
Main Methods:
- Administration of imipenem (i.p. and i.c.v.) to DBA/2 mice to induce seizures.
- Assessment of anticonvulsant activity of drugs including MK-801, CGP 39551, CPPene, CCP, NBQX, Ifenprodil, Msc, AP7, gamma-D-GAMS, KYNA, and CNQX.
- Comparative analysis of anticonvulsant efficacy based on drug administration route and specific receptor targets.
Main Results:
- Imipenem administration induced seizures in DBA/2 mice, with varying susceptibility based on administration route.
- The anticonvulsant order differed between i.p. and i.c.v. administration, highlighting route-dependent effects.
- Excitatory amino acid antagonists and muscimol demonstrated significant anticonvulsant activity, suggesting involvement of NMDA and GABAergic pathways in imipenem neurotoxicity. Ifenprodil's lack of effect indicated minimal role for the NMDA receptor polyamine site.
Conclusions:
- Imipenem-induced seizures in DBA/2 mice involve complex mechanisms potentially mediated by excitatory amino acid neurotransmission and inhibition of GABAergic pathways.
- Antagonists of excitatory amino acids and agonists of GABAA receptors can effectively mitigate imipenem-induced seizures.
- These findings underscore the importance of considering neurochemical interactions when assessing the central nervous system effects of carbapenem antibiotics.