Effects of some excitatory amino acid antagonists and drugs enhancing gamma-aminobutyric acid neurotransmission on pefloxacin-induced seizures in DBA/2 mice

Abstract

The behavioral and convulsant effects of pefloxacin (PEFLO), a quinolone derivative, were studied after intraperitoneal (i.p.) administration to Dilute Brown Agouti DBA/2J (DBA/2) mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid (EAA) antagonists acting at N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors and of some compounds enhancing gamma-aminobutyric acid (GABA)-ergic transmission against seizures induced by PEFLO were also evaluated. The present study demonstrated that both groups of compounds administered i.p. or intracerebroventricularly were able to protect against seizures induced by PEFLO. However, ifenprodil and (+/-)-alpha-(chlorophenyl)-4-[(4-fluorophenyl)methyl]-1-piperidine-ethan ol (SL 82.0715), two compounds acting on the polyamine site of the NMDA receptor complex, were unable to provide any protection. The relationship between the different sites of action and the anticonvulsant activities of these derivatives were discussed. Although the main mechanisms of PEFLO-induced seizures cannot be easily determined, potential interactions with the receptors of EAA exist. In fact, antagonists of EAA, and in particular, those acting at NMDA receptors, were able to increase the threshold for the seizures or to prevent the seizures induced by PEFLO, while compounds acting at the polyamine site did not provide any protection. The AMPA-KA receptor antagonists were also able to exert anticonvulsant activity, but with minor potency in comparison to those of NMDA antagonists. In addition, the fact that compounds enhancing GABA-ergic neurotransmission were also able to protect the mice against seizures induced by PEFLO suggests an involvement of GABA system.

Pharmacokinetic-Pharmacodynamic Contributions to the Convulsant Activity of Fluoroquinolones in Rats

“…Discrepancies between in vitro and in vivo data may have several origins. One possible explanation is that GABA A is not solely responsible for the convulsant activities of FQs but that other mediators such as glutamate and adenosine may also be involved (11,12,31). It is also possible that the relative contribution of each type of mediator is not the same for all FQs, which possibly explains the differences observed in the types of seizures.…”

Psychosis as an adverse effect of antibiotics

“…Additionally, fluoroquinolones are moderately lipophilic allowing them to readily penetrate the blood brain barrier and exert neurotoxic effects ( Nau et al., 2010 ). Alternatively, fluoroquinolones may directly activate NMDA receptors, as one animal study found that blocking NMDA receptors in mice prevented the occurrence of fluoroquinolone-induced neurotoxicity ( De Sarro et al., 1997 ). Metronidazole-induced neurotoxicity is also thought to be caused by its inhibitory effect on the GABA receptor.…”

Synthesis, Antibacterial Activity, and Toxicity of 7-(Isoindolin-5-yl)-4-oxoquinoline-3-carboxylic Acids

“…Convulsion-inducing activity was evaluated according to the procedure of Haley and McCormick [26,27] using four-weekold male ICR mice (25−30 g body weight, n = 6−10). Briefly, an aliquot (10 µl) of a testing sample solution, which was prepared by dissolution in 0.1 mol/l NaOH followed by dilution with saline, was injected into the brain using a Hamilton microsyringe No.…”