Quinolones and fenbufen interact with GABAA receptor in dissociated hippocampal cells of rat.
1. Interaction of quinolone antibiotics and the anti-inflammatory agent fenbufen with the gamma-aminobutyric acid-A (GABAA) receptor-chloride channel complex in pyramidal neurons freshly dissociated from the hippocampal CA1 region of the rats was investigated in whole-cell mode, using the patch-clamp technique under voltage-clamp conditions. 2. Quinolones in clinical doses had no effects on the GABA-gated Cl- current (ICl) but slightly suppressed the response at concentrations greater than 10(-5) M. A metabolite of fenbufen, 4-biphenylacetic acid (BPA), also had little effect on the GABA response at therapeutic concentrations. 3. Coadministration of one of quinolones and BPA suppressed the GABA-gated ICl with increase in each of them in a concentration-dependent manner, and there was a parallel shift of the concentration-response curve for GABA to the right but with no effect on the maximum response, thereby indicating a competitive antagonism. The inhibitory potency of antibiotics in combination with BPA was in the order of norfloxacin much greater than enoxacin greater than cyprofloxacin greater than pipemidic acid much greater than ofloxacin greater than cinoxacin = piromidic acid = nalidixic acid = 0. 4. Norfloxacin and BPA, administered simultaneously, also strongly suppressed pentobarbital sodium (PB)-gated ICl, but they did not act on benzodiazepine (BZP) receptors. 5. Both GABA- and PB-induced ICls reversed at the Cl- equilibrium potential (ECl). In the presence of BPA, the quinolone-induced inhibition of GABA-gated ICls showed no voltage dependence. 6. It was concluded that, in the presence of an anti-inflammatory agent, the quinolone antibiotics decrease the affinity of GABAA receptors, the result being induction of epileptogenic neurotoxicities.
Akaike
N
N
Department of Neurophysiology, Tohoku University School of Medicine, Sendai, Japan.
Shirasaki
T
T
Yakushiji
T
T
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018118:Chloride Channels; D004347:Drug Interactions; D004594:Electrophysiology / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010424:Pentobarbital / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology*; D011712:Pyramidal Tracts / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D042462:4-Quinolones; D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018118:Chloride Channels; D007473:Ion Channels; D008565:Membrane Proteins; D010654:Phenylbutyrates; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C010725:fenbufen; D010424:Pentobarbital