Norfloxacin-Induced Electroencephalogram Alteration and Seizures in Rats Are Not Triggered by Enhanced Levels of Intracerebral Glutamate

Abstract

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram (EEG) effect was combined with intracerebral glutamate determinations using microdialysis for rats receiving norfloxacin intravenously (150 mg/kg of body weight). The EEG effect (accompanied by tremors and seizures) was consistently observed without glutamate level modifications. Therefore, norfloxacin-inducted seizures are not triggered by intracerebral glutamate level enhancement.Fluoroquinolone antibiotics may induce central nervous system excitatory side effects, including anxiety, nervousness, hallucination, and even seizures on rare occasions (3, 13). It is usually asserted that these excitatory side effects result from inhibition of GABA (␥-aminobutyric acid) binding to its receptors (1, 11). Using intracerebral microdialysis, however, Smolders et al. have previously observed in conscious rats norfloxacin-induced convulsions accompanied not by any apparent effect on the extracellular hippocampal GABA levels but rather by enhanced intracerebral glutamate concentrations (10). Studies of the relationship between glutamate concentrations and epileptic seizures have yielded conflicting observations, as recently reviewed (12). Smolders et al. have hypothesized that enhanced glutamate levels might be essential for the induction of norfloxacin seizures (10), but it could also be argued that the generation, spreading, and maintenance of seizures eventually leads to glutamate release and elevation (9). Quantitative electroencephalogram (EEG) recording combined with intracerebral microdialysis offers a unique opportunity to address this question. In rats treated with imipenem (5) and norfloxacin (2), increases in the total power of the EEG signal are related to behavioral modifications and the occurrence of tremor and partial seizures and can therefore be considered an appropriate surrogate pharmacodynamic (PD) end point for the investigation of the convulsant activity of these antibiotics in rats. Furthermore, the kinetics of this effect can be very precisely evaluated using pharmacokinetic (PK)-PD modeling techniques (2, 5).The objective of this study was therefore to combine quantitative EEG recording (for the characterization of seizure induction and maintenance) with intracerebral microdialysis using the hippocampus (for the measurement of glutamate levels) of rats (after the administration of norfloxacin) to look for a causality relationship between the two factors. The experiment was conducted in accordance with the Principles of Laboratory Animal Care (National Institutes of Health), and ethical approval was obtained from the Animal Ethics Committee of the Faculty of Pharmacy (BHE 2001/12/ AE). Norfloxacin was obtained from Sigma (Saint-Quentin Fallavier, France), and a salt was prepared as previously described (4). L-glutamate standards were supplied by Sigma. All chemicals used were of analytical grade, and the analytical solvents used were of high-performance liquid chromatography grade. Six male Sprague-Dawley rats (weighing 299 Ϯ 15 g)...

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