INHIBITORY EFFECT OF NEW QUINOLONES ON GABA(A) RECEPTOR-MEDIATED RESPONSE AND ITS POTENTIATION WITH FELBINAC IN XENOPUS OOCYTES INJECTED WITH MOUSE-BRAIN MESSENGER-RNA - CORRELATION WITH CONVULSIVE POTENCY IN-VIVO
J. Kawakami et al., INHIBITORY EFFECT OF NEW QUINOLONES ON GABA(A) RECEPTOR-MEDIATED RESPONSE AND ITS POTENTIATION WITH FELBINAC IN XENOPUS OOCYTES INJECTED WITH MOUSE-BRAIN MESSENGER-RNA - CORRELATION WITH CONVULSIVE POTENCY IN-VIVO, Toxicology and applied pharmacology, 145(2), 1997, pp. 246-254
Convulsions induced by the interaction of new quinolone antimicrobial
agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were pr
eviously reported, and blockade of GABA(A) receptor by NQs and its pot
entiation with NSAIDs were considered as one of its possible mechanism
s. 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 relations
hip 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 sacr
ificing innumerous animals. Glutamic acid, kainic acid, quisqualic aci
d, NMDA, and serotonin-induced currents were not modified by ENX of NQ
s and/or FLB of NSAIDs, while glycine-and ACh-induced currents were sl
ightly inhibited. GABA (10 mu M)-induced current was inhibited by norf
loxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of
17, 33, 58, and 280 mu M, respectively. IC50 of NQs decreased to 1/3 (
OFLX)-1/165 (NFLX) in the presence of 10 mu M FLB, while FLB did not m
odulate the GABA response in the absence of NQs. CSF concentration of
ENX at the time of convulsion in clinical situation approximated the I
C50 of ENX for the GABA response. The increase of incidence for NQs-in
duced convulsion by concomitant NSAIDs in vivo could also be explained
by the potentiation of inhibitory effects of NQs with FLB in the norm
al range of CSF concentration of these drugs. We also examined convuls
ive potency (threshold dose for convulsion) in CNS by intracerebral in
fusion of NQs to mice with or without FLB pretreatment, and significan
t correlations between the convulsive potencies and IC50 of NQs for th
e GABA response were observed. These findings suggested that the block
ade 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 GABAA r
eceptor in vitro using the Xenopus oocytes translation system of exoge
nous mRNA. (C) 1997 Academic Press.