title: Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins.
abstract: There is accumulating evidence that most beta-lactam antibiotics (i.e., cephalosporins and penicillins) have some degree of convulsive activity, both in laboratory animals as well as in clinical settings. The proposed mechanism is suppression of inhibitory postsynaptic responses, mainly mediated by gamma-amino butyric acid (GABA)(A)-receptors (GABA(A)-R). However, comprehensive studies on the convulsive activities of various beta-lactam antibiotics in vivo and in vitro have not been performed. We have therefore examined the convulsive activities of seven different cephalosporins using both in vivo and in vitro models: intracerebroventricular (ICV) administration in mouse; [(3)H]muscimol binding assay (BA) in mouse brain synaptosome; and inhibition of recombinant mouse alpha1beta2gamma2s GABA(A)-Rs in Xenopus oocyte (GR). The rank orders of convulsive activities in mouse (cefazolin>cefoselis>cefotiam>cefpirome>cefepime>ceftazidime>cefozopran) correlated with those of inhibitory potencies on [(3)H]muscimol binding and GABA-induced currents of GABA(A)-R in vitro, with correlation coefficients of ICV:GR, ICV:BA and BA:GR of 0.882, 0.821 and 0.832, respectively. In contrast, none of the antibiotics had affinities for N-methyl-D-aspartate (NMDA) receptors nor facilitatory actions on NMDA receptor-mediated current in oocytes. These results clearly demonstrate that the mechanism of cephalosporin-induced convulsions is mediated predominantly through the inhibition of GABA(A)-R function and not through NMDA receptor modulation.
authors.affiliation: Department of Anesthesiology, Osaka University Medical School, 2-2, Yamada-oka, Suita, 565-0871, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Uchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Mashimo
authors.forename: Shunji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hatano
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Takao
authors.initials: T
authors.lastname: Terai
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002511:Cephalosporins / Q000378:metabolism* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D058787:GABA-A Receptor Antagonists; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate