Effects of manipulation of N-methyl-D-aspartate receptors on imipenem/cilastatin-induced seizures in rats.
OBJECTIVE
Epileptic seizures have been reported in patients on imipenem/cilastatin (Imi/Cil) therapy. To investigate contribution of N-methyl-D-aspartate (NMDA) receptors in inducing imipenem/cilastatin (Imi/Cil) seizures, the effects of competitive NMDA antagonist, APV [(+/-)-2-amino-5-phosphonovaleric acid], non-competitive NMDA antagonist remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamidel, and glycine receptor partial agonist HA-966 [(+/-)-(3-amino-1-hydroxypyrrolid-2-one)] on electroencephalographic (EEG) activity and behaviour were studied in rats.


METHODS
Adult male Wistar albino rats were implanted with electrodes and cannulae were placed into the right lateral ventricle. Animals were divided into five groups: (i) saline (icv)+Imi/Cil (ii) APV (0.2 micromol)+Imi/Cil, (iii) APV (0.4 micromol)+Imi/Cil, (iv) remacemide (100 mg/kg, ip)+Imi/Cil, and (v) HA-966 (200 microg, icv)+Imi/Cil. The drugs were administered 30 min before icv injection of Imi/Cil (100/100 microg), and their effects on incidence of seizures, latencies to EEG changes and convulsions, severity, lethality and time to lethal outcome were studied.


RESULTS
Imi/Cil provoked complete seizure response in all rats and all animals died within 10-18 min after the injection. EEG epileptiform activity preceded behavioral seizures. Clonic-tonic seizures were characterized by continuous bursts of high frequency high amplitude spikes in the EEG. The dose of 0.2 micromol of APV prolonged only the latency to the first EEG changes, while 0.4 micromol dose significantly influenced all seizure parameters. HA-966 increased only the latency to Imi/Cil-induced convulsions, while remacemide had no significant effect on seizure parameters.


CONCLUSIONS
The results suggested that excitatory neurotransmission contributed to the generation and/or propagation of Imi/Cil-induced seizures in rats, and that the effects of NMDA antagonists depended on a particular binding site within the NMDA receptor complex, and affinity to that site.
Zivanovic
Dragana
D
Institute of Physiology, School of Medicine, University of Belgrade, Belgrade, Serbia. zdragana@afrodita.rcub.bg.ac.yu
Lovic
Olivera Stanoj
OS
Susic
Veselinka
V
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D015377:Cilastatin / Q000633:toxicity; D000077728:Cilastatin, Imipenem Drug Combination; D004338:Drug Combinations; D004569:Electroencephalography / Q000187:drug effects*; D015378:Imipenem / Q000633:toxicity; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000081:Acetamides; D004338:Drug Combinations; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D015377:Cilastatin; D015378:Imipenem; C056639:2-amino-5-phosphopentanoic acid; D000077728:Cilastatin, Imipenem Drug Combination; C067553:remacemide; C001369:1-hydroxy-3-amino-2-pyrrolidone; D014633:Valine