Effects of novel 6-desfluoroquinolones and classic quinolones on pentylenetetrazole-induced seizures in mice

Abstract

There have been several reports that convulsions, although rare, occur in patients who receive fluoroquinolones. In this study, the proconvulsant effects exhibited by a novel series of 6-desfluoroquinolones and some classic quinolones on pentylenetetrazole (PTZ)-induced seizures in mice were evaluated and compared. Animals were intraperitoneally injected with vehicle or quinolone derivatives (5 to 100 microg/g of body weight) 30 min before the subcutaneous (s.c.) administration of PTZ (40 microg/g). In each experiment, mice were then observed for 1 h to monitor for the incidence and onset of clonic seizures. The order of proconvulsant activity in our epileptic model was MF5184 > MF5187 > pefloxacin > MF5189 > ofloxacin > ciprofloxacin > MF5140 > MF5181 > MF5137 > rufloxacin > MF5143 > MF5158 > MF5191 > MF5128 > MF5138 > cinoxacin > MF5142 > norfloxacin > nalidixic acid. The relationship between the chemical structure and the proconvulsant activity of 6-desfluoroquinolone derivatives was studied. We observed that, in terms of toxicity to the central nervous system (CNS), besides the heterocyclic side chain (moiety) at the C-7 position, the C-6 substituent also appears to play an important role. In particular, a hydrogen at the C-6 position seemed to be responsible for major neurotoxic activity in comparison to an amino group located in the same position. The relationship between lipophilicity and proconvulsant activity was also investigated. We did not find any clear relationship between a higher level of lipophilicity and major proconvulsant properties. Although the principal mechanism by which quinolones induce potentiation of the proconvulsant effects of PTZ cannot be easily determined, it is possible that the convulsions are caused by drug interactions, because both PTZ and quinolones are believed to increase excitation of the CNS by inhibition of gamma-aminobutyric acid binding to receptors.

FIG. 1

Incidence of clonic convulsions induced by different doses of PTZ (10 to 90 μg/g, s.c.) in ICR mice.

FIG. 2

Dose-response curves illustrating the effects of the administration of different doses (10 to 100 μg/g, i.p.) of quinolone derivatives followed 30 min later by a dose of PTZ (40 μg/g, s.c.) in mice (10 animals for each group).

FIG. 3

Seizure latency of different quinolones i.p. injected 30 min before PTZ (40 μg/g, s.c.) in mice (10 animals for each group) Open columns in panel A indicate control group (vehicle plus PTZ); other columns indicate quinolone derivatives plus PTZ. ∗, significantly different (P < 0.05) from the value for the group receiving vehicle plus PTZ.

FIG. 4

Electrocortical patterns from the right and left frontoparietal cortex (rCx and lCx) after administration of vehicle (i.p.) plus PTZ (40 μg/g, s.c.) (A, B, C, and D) or PFX (80 μg/g, i.p.) plus PTZ (40 μg/g, s.c.) (A1, B1, C1, and D1) in mice. Electrocorticographic recordings were made 15 min after the injection of vehicle or PFX (A and A1), and 20 min (B and B1), 60 min (C and C1), and 120 min (D and D1) after the injection of PTZ.

FIG. 5

Electrocortical patterns from the right and left frontoparietal cortex (rCx and lCx) after administration of MF5184 (80 μg/g, i.p.) plus PTZ (40 μg/g, s.c.) (A, B, C, and D) or MF5187 (80 μg/g, i.p.) plus PTZ (40 μg/g, s.c.) (A1, B1, C1, and D1) in mice. Electrocorticographic recordings were made 15 min after the injection of MF5184 and MF5187 (A and A1) and 20 min (B and B1), 60 min (C and C1), and 120 min (D and D1) after the injection of PTZ.