Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: correlation with convulsive potency in vivo.
Convulsions induced by the interaction of new quinolone antimicrobial agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported, and blockade of GABA(A) receptor by NQs and its potentiation with NSAIDs were considered as one of its possible mechanisms. However, useful methodology for prediction of convulsive potencies of NQs with or without NSAIDs in vivo based on in vitro screening was not established. Therefore, we applied the Xenopus oocytes translation system of exogenous messenger RNA (mRNA) to examine the mechanism of convulsion induced by interaction of NQs and NSAIDs, and the relationship between convulsive potencies in vivo and inhibitory effect on GABA-induced current response in vitro was investigated. This system also has alternative possibility for the in vivo toxicological studies sacrificing innumerous animals. Glutamic acid, kainic acid, quisqualic acid, NMDA, and serotonin-induced currents were not modified by ENX of NQs and/or FLB of NSAIDs, while glycine- and ACh-induced currents were slightly inhibited. GABA (10 microM)-induced current was inhibited by norfloxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of 17, 33, 58, and 280 microM, respectively. IC50 of NQs decreased to 1/3 (OFLX)-1/165 (NFLX) in the presence of 10 microM FLB, while FLB did not modulate the GABA response in the absence of NQs. CSF concentration of ENX at the time of convulsion in clinical situation approximated the IC50 of ENX for the GABA response. The increase of incidence for NQs-induced convulsion by concomitant NSAIDs in vivo could also be explained by the potentiation of inhibitory effects of NQs with FLB in the normal range of CSF concentration of these drugs. We also examined convulsive potency (threshold dose for convulsion) in CNS by intracerebral infusion of NQs to mice with or without FLB pretreatment, and significant correlations between the convulsive potencies and IC50 of NQs for the GABA response were observed. These findings suggested that the blockade of GABA-ersic neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the Xenopus oocytes translation system of exogenous mRNA.
Kawakami
J
J
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Yamamoto
K
K
Asanuma
A
A
Yanagisawa
K
K
Sawada
Y
Y
Iga
T
T
D000818:Animals; D000890:Anti-Infective Agents / Q000134:cerebrospinal fluid / Q000633:toxicity*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D001640:Bicuculline / Q000633:toxicity; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000134:cerebrospinal fluid / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015365:Enoxacin / Q000134:cerebrospinal fluid / Q000633:toxicity; D005260:Female; D058787:GABA-A Receptor Antagonists; D007276:Injections, Intraventricular; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008845:Microinjections; D009643:Norfloxacin / Q000134:cerebrospinal fluid / Q000633:toxicity; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010648:Phenylacetates / Q000633:toxicity*; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced*; D014982:Xenopus laevis
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D058787:GABA-A Receptor Antagonists; D010648:Phenylacetates; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D015365:Enoxacin; C012776:biphenylylacetic acid; D002939:Ciprofloxacin; D009643:Norfloxacin; D001640:Bicuculline