Low neurotoxicity of LJC 10,627, a novel 1 beta-methyl carbapenem antibiotic: inhibition of gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in relation to lack of central nervous system toxicity in rats.
The toxicity of LJC 10,627 to the central nervous system of rats was evaluated by examining the effects of the compound on gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in rat synaptic membranes and on the induction of behavioral convulsions by intraventricular administration to rats. The concentrations of this compound needed to inhibit specific [3H]muscimol binding, specific [3H]diazepam binding, and specific [3H]strychnine binding were greater than those of imipenem, as demonstrated by the 50% inhibitory concentrations (IC50S of LJC 10,627, greater than 10 mM for each; IC50S of imipenem, 0.6, 1.9, and 0.2 mM, respectively). These results reflect the fact that LJC 10,627 does not evoke severe convulsions or cause death, even when it is administered intraventricularly at a high dose (300 micrograms per rat), and suggest that the low neurotoxic potential of LJC 10,627 may be attributed to the chemical structure of this compound, which has a methyl radical at the 1 beta site and a triazolium radical at the side chain of the second site.
Biological Research Laboratories Lederle (Japan), Ltd., Saitama.
M
M
Hikida
Y
Y
Masukawa
K
K
Nishiki
N
N
Inomata
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D003975:Diazepam / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D009118:Muscimol / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced; D013331:Strychnine / Q000378:metabolism; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D013845:Thienamycins / Q000008:administration & dosage / Q000633:toxicity*
D058787:GABA-A Receptor Antagonists; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D013845:Thienamycins; D009118:Muscimol; D013331:Strychnine; D003975:Diazepam; C065257:biapenem