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Quantitation of GABAA receptor inhibition required for quinolone-induced convulsions in mice
Y Tsutomi1, K Matsubayashi, K Akahane
1Exploratory Research Laboratories I. Daiichi Pharmaceutical Co., Tokyo, Japan.
Abstract:
We quantified the amount of inhibition of gamma-aminobutyric acid (GABA)A receptor binding required for the onset of convulsions induced by ciprofloxacin in combination with biphenylacetic acid (BPAA) in mice. In fasting mice iv ciprofloxacin given 30 min after oral BPAA (50 mg/kg) induced convulsions at doses of 40 mg/kg or above. In contrast, ofloxacin caused no convulsions even at 100 mg/kg, the highest dose tested. When mice received 40 mg/kg of ciprofloxacin or ofloxacin, maximal brain concentrations of each quinolone at 30 min were 0.37 or 1.97 micrograms/g, respectively. These brain concentrations of ciprofloxacin and ofloxacin were not affected by combination with BPAA. In the presence of ciprofloxacin and BPAA (at brain tissue concentrations which induced convulsions), the binding of 3H-muscimol to GABAA receptor sites was inhibited by approximately 30%. Using results from a similar binding study, an impracticable iv dose of ofloxacin (500 mg/kg) was estimated to be required to inhibit GABAA receptor binding by 30%, and therefore to induce similar convulsions to those seen with ciprofloxacin at a dose of 40 mg/kg. These results may indicate that epileptic convulsions occur when ciprofloxacin and BPAA interact with each other to antagonize at least 30% of GABAA receptor binding in mice, and provide evidence for a significant role of GABAA receptor inhibition in the occurrence of quinolone-induced convulsions.
Insights
Ciprofloxacin combined with biphenylacetic acid (BPAA) induced convulsions in mice by inhibiting gamma-aminobutyric acid (GABA)A receptors. This combination requires approximately 30% GABAA receptor inhibition for seizure onset.
Area of Science:
- Neuropharmacology
- Toxicology
Background:
- Quinolone antibiotics, like ciprofloxacin, can induce convulsions.
- The mechanism underlying quinolone-induced seizures, particularly in combination with other drugs, requires further elucidation.
Purpose of the Study:
- To quantify the degree of gamma-aminobutyric acid (GABA)A receptor inhibition necessary for ciprofloxacin-induced convulsions when co-administered with biphenylacetic acid (BPAA) in mice.
- To compare the convulsant potential of ciprofloxacin and ofloxacin in combination with BPAA.
Main Methods:
- Mice were administered oral BPAA followed by intravenous ciprofloxacin or ofloxacin.
- Convulsions were monitored, and maximal brain concentrations of quinolones were measured.
- In vitro binding assays quantified the inhibition of 3H-muscimol binding to GABAA receptor sites.
Main Results:
- Ciprofloxacin (≥40 mg/kg) plus BPAA induced convulsions, while ofloxacin did not at tested doses.
- Convulsions induced by ciprofloxacin and BPAA were associated with approximately 30% inhibition of GABAA receptor binding.
- Estimated high doses of ofloxacin would be required to achieve similar GABAA receptor inhibition.
Conclusions:
- Ciprofloxacin and BPAA interact to antagonize GABAA receptor binding, with at least 30% inhibition being critical for seizure induction in mice.
- GABAA receptor inhibition plays a significant role in the occurrence of quinolone-induced convulsions.