Neurochemical Studies on Quinolone Antibiotics: Effects on Glutamate, GABA and Adenosine Systems in Mammalian CNS

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Abstract
Quinolone antibiotics, which can be proconvulsant in susceptible patients, were found to inhibit the specific binding of the adenosine receptor ligands L-3H-N6-phenylisopropyladenosine (L-3H-PIA) and 3H-N-ethylcarboxamidoadenosine (3H-NECA) to rat brain synaptic membranes. The inhibitions were concentration dependent, and for both ligands the order of potency was rosoxacin > nalidixic acid > oxolinic acid ≥ ciprofloxacin > norfloxacin > enoxacin: IC20 values (concentrations causing a 20% inhibition of specific binding) ranged from 30–35 μM to 1–3 mM. Hill coefficients were approximately 0.5, suggesting that the compounds are probably antagonists at these sites. Most of the compounds did not alter 3H-diazepam binding directly, although rosoxacin showed relatively strong, and enoxacin weak, concentration-dependent inhibition. At 50 μM the compounds enhanced the maximal γ-aminobutyric acid (GABA) activation of 3H-diazepam binding to varying degrees, without altering the EC50 of activation, whereas at 200 μM they tended to reduce GABA activation. Most noteworthy was the large increase in GABA-stimulated 3H-diazepam binding caused by 50 μM nalidixic acid. The compounds did not alter the Ca2+/Cl−-dependent binding of 3H-glutamate, nor of the binding of the glutamate site-selective ligands 3H-kainate and α-3H-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (3H-AMPA); the uptake of the non-metabolized glutamate analogue D-3H-aspartate by cortical homogenates was also unaffected. The CNS side effects of these antibiotics may result, in part, from interaction with sites which mediate the inhibitory neurotransmission of adenosine and, possibly, GABA.