International Journal of Antimicrobial Agents 12 (1999) 239 – 244 www.elsevier.com/locate/isc
Original article
Enhanced susceptibility of pentylenetetrazole kindled mice to quinolone effects Angela De Sarro a,*, Francesco Naccari b, Giovambattista De Sarro c b
a Institute of Pharmacology, School of Medicine, Policlinico Uni6ersitario, 98100 Messina, Italy Department of Clinical Medicine and Veterinary Pharmacology, School of Veterinary Medicine, Uni6ersity of Messina, Messina, Italy c Department of Experimental and Clinical Medicine, School of Medicine, Uni6ersity of Catanzaro, Catanzaro, Italy
Received 26 January 1999; accepted 17 February 1999
Abstract The present study was designed to examine the ability of different quinolones to affect the seizure severity and the latency of development of chemical kindling produced by repeated treatment using a subconvulsant dose of pentylenetetrazole (PTZ). A group of mice (kindled control) were treated subcutaneously (s.c.) with vehicle +PTZ (30 mg/kg, three times a week) for 6 consecutive weeks and the changes in excitability associated with the kindling state were observed over the following 2 h. A second group of mice were injected intraperitoneally (i.p.) with the following quinolone derivatives, ciprofloxacin (ciprox), pefloxacin (peflox), ofloxacin (oflox), cinoxacin (cinox), nalidixic acid (nalidixic), 1-cyclopropyl-6-amino-7-tetrahydroisoquinoline-8-methyl-4oxo-1,4-dihydroquinoline-3-carboxylic acid (M5) and 1-cyclopropyl-7-tetrahydro-isoquinoline-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (MH5) at a dose of 20 mg/kg 15 min before receiving a subconvulsant dose of PTZ (30 mg/kg, s.c.). The results showed that pretreatment with some of the quinolones tested facilitated the development of kindling to PTZ-induced seizures. In particular, ciprox, peflox, oflox, M5 and MH5 derivatives variously increased the development of kindling to PTZ induced seizures, whilst cinox and nalidix did not significantly affect it. Additionally we determined whether the enhanced susceptibility of kindled mice only occurred after relatively short intervals following the last seizure or whether it was a more permanent phenomenon. For the study of the persistence of kindling, the animals were rechallenged with the kindling stimulus (PTZ 25 mg/kg, s.c.) 15 and 30 days after the last injection of the chronic treatment with PTZ (30 mg/kg, s.c.) and the behavioural changes in the kindled mice were compared with the control ones (chronically treated with vehicle). The present data demonstrated that kindling produced long-lasting alterations, substantiating that epileptogenesis initiated by kindling renders the brain more susceptible to central nervous system (CNS) side effects of quinolones. An interaction between PTZ and quinolone derivatives which involves either an inhibition of g-aminobutyric acid (GABA) neurotransmission or/and an increase in the function of the excitatory amino acid (EAA) system is suggested. © 1999 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Quinolones; Kindling; Pentylenetetrazole; Seizures; Epilepsy; Mice
1. Introduction Some reports indicate a possible incidence of central nervous system (CNS) adverse reactions and drug interactions following the use of quinolones. Convulsions
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have been reported more frequently in individuals with an underlying CNS predisposition and in patients who received both fluoroquinolones and either theophylline or certain nonsteroidal antinflammatory drugs [1,2]. In our previous studies a convulsant behavioural pattern following the concomitant administration of quinolones and theophylline in rats [3,4] was shown. Also demonstrated was the fact that quinolones potentiated the convulsant effects elicited by cefazolin or imipenem in mice [5,6]. It is well-known that in vitro quinolones
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neumoniae strains. In contrast, exposure to sub-MICs of either tylosin or apramycin markedly reduced the production of capsular material of both isolates (Table membranes [7–9] and so, as GABA antagonists, quinolones could be expected to be proconvulsant when given to animals in combination with an agent that blocks GABA mediated inhibition such as pentylenetetrazole (PTZ) [10,11]. Previous studies have demonstrated that some quinolones enhance the epileptogenic properties of PTZ in mice [12,13]. The purpose of this study was to compare the ability of some quinolone derivatives to increase the seizure severity in a chemical kindling model of epilepsy: pentylenetrazole-induced kindling. Kindling represents a useful experimental model for the study of the convulsive component of epilepsy and the development and evaluation of antiepileptic drugs [14]. The kindling phenomenon is an increased susceptibility to electrically-induced convulsions after repeated exposure to electrical stimuli [15], but chemical kindling also occurs and several studies of kindling with PTZ in rats and mice have been reported [16 – 18]. It is interesting to note that the development of kindling is directly proportional to the dose and so the repeated administration of subconvulsant doses of PTZ induces a gradual increase in CNS excitability such that fully kindled animals develop convulsions in response to a dose of PTZ that was initially subconvulsant [18]. Additionally, kindling effects are cumulative with repeated exposure and once developed, persist for several days or even for the life of the animal [19]. The present study provides an evaluation of the ability of different quinolone derivatives to affect the development of behavioural seizures in PTZ kindled mice. We also investigated whether the enhanced susceptibility of PTZ kindled mice to quinolone adverse effects occurs only after relatively short intervals following the last seizure or is a more permanent phenomenon.
2. Materials and methods
2.1. Animals Male ICR mice (20 – 24 g, 42 – 48 days old) were purchased from Nossan (Correzzana, Milano, Italy), and during the quarantine period lasting at least 10 days, were housed in wire-mesh cages and kept in an air-conditioned room (temperature, 2392°C; humidity, 559 15%; light cycle, 12 h/day). They were allowed free access to commercial chow (Nossan, Correzzana, Milano, Italy) and tap water and were acclimatised to laboratory conditions until the experiments were carried out. After the quarantine period, the mice were randomly assigned to each experimental group (20 mice for each dose).
Procedures involving animals and their care were carried out according to the Institutional guidelines and the European Communities Council directives of laws and policies.
2.2. Experimental procedure A group of mice (kindled control) was injected intraperitoneally (i.p.). with the vehicle (10 ml/kg) and 15 min later the animals were subcutaneously (s.c.) injected with PTZ (30 mg/kg in a volume of 10 ml/kg at 09:00). Kindling was produced by the injection of PTZ once every 2 days for up to 6 consecutive weeks. A second group of kindled mice were injected i.p. with different quinolone derivatives (cinox, nalidixic, peflox, ciprox, oflox, M5 and MH5 20 mg/kg) 15 min prior to the injection of PTZ (30 mg/kg, s.c.). A third group of matched control mice were given the vehicle at the same volume (10 ml/kg) for the same period. In each experiment, the animals were placed in a plexiglass box (0.040× 0.04× 0.03 m) and observed for the following 120 min for the incidence and onset of convulsions. The intensity of the seizure response was scored on the following scale: 0, no response; 1, mouth and facial jerks; 2, nodding or myoclonic body jerks; 3, forelimb clonus; 4, rearing, falling down, hindlimb clonus and forelimb tonus; and 5, tonic extension of hindlimb, status epilepticus and/or death. The maximum response was recorded for each animal. The mice in each group were also observed for latency of seizure response. Any mouse that convulsed in response to the kindling treatment on day 1 was removed from the study. When a mouse exhibited stage four seizures three times it was considered fully kindled and treatment was discontinued. On the same day, the treatment of one mouse in each experimental group was discontinued in order to have comparable withdrawal periods across treatments. The mice who fulfilled the kindling criteria after 6 weeks of repeated treatment were considered completely protected and not used in the subsequent seizure studies. The mice whose treatment was discontinued after the kindling criteria were achieved were assigned the score of their last week of treatment for each of the remaining weeks in the calculation of the results.
2.3. Challenge with PTZ For the study of the persistence of kindling status two independent challenge experiments were performed using PTZ (25 mg/kg, s.c.) 15 and 30 days after withdrawal (achieved by the removal of both the quinolones and/or PTZ) from the last injection of PTZ (30 mg/kg, s.c.) treatment. The mice were observed for 120 min after injection in order to determine the incidence of convulsions. Experiments were carried out using control mice (at least n=10) chronically treated with vehi-
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cle, kindled control mice (at least n = 10) chronically treated with vehicle+PTZ and mice (at least n = 10 for each group) chronically treated with each quinolone+ PTZ. These animals were not used in subsequent studies. For ethical reasons at the end of each experiment section the animals which showed status epilepticus were killed by ether anaesthesia.
2.4. Statistical analysis Statistical comparisons of vehicle+ PTZ-kindled mice and kindled mice pretreated with quinolones were made using Fisher’s exact probability test (incidence of seizure phases) and the Mann – Whitney U test was used to compare median seizure score data from the different groups. The delay of the onset of seizures was evaluated using Bonferroni’s corrected Student’s t-test.
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affect it. None of the quinolone derivatives exhibited any convulsant effects when given alone in the same doses and under the same experimental conditions (data not shown).
3.1. Challenge with PTZ The challenge experiments carried out with PTZ (25 mg/kg, s.c.) demonstrated that PTZ elicited seizures in eight out of 10 animals receiving vehicle+ PTZ, in seven out of 10 animals treated with nalidix + PTZ or cinox+PTZ, in nine out of 10 animals treated with oflox+ PTZ or M5+ PTZ, 11 out of 12 mice treated with ciprox+ PTZ, peflox+ PTZ or MH5+ PTZ and in 1 out of 20 mice treated with vehicle alone (Fig. 3A and B). No significant differences were observed between the groups of mice rechallenged with PTZ (25 mg/kg, s.c.) (Fig. 4) 15 or 30 days after the end of the chronic treatment. These results indicated that the kin-
2.5. Drugs Pefloxacin mesylate (peflox) was purchased from Rhone-Poulenc Pharma (Milano, Italy), cinoxacin (cinox) from Eli Lilly (Indianapolis, USA), ciprofloxacin hydrochloride (ciprox) from Bayer (Leverkusen, Germany), ofloxacin (oflox) from Sigma Tau Laboratories (Pomezia, Italy), nalidixic acid (nalidix) and pentylenetetrazole (PTZ) from Sigma (Milano, Italy). The compounds 1-cyclopropyl-6-amino-7tetrahydroisoquinoline-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (M5) and 1 cyclopropyl-7-tetrahydroisoquinoline-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (MH5) were synthesized by Professor Cecchetti [20] of the Istituto di Chimica e Tecnologia del Farmaco, (University of Perugia, Italy). The compounds were dissolved in carboxymethylcellulose 5%. All drug solutions, injected at a volume of 10 ml/kg body weight, were prepared immediately before injection.
3. Results The data shown in Fig. 1A and B represent the effects of treatment with a subconvulsant dose (30 mg/kg) of PTZ every 2 days on the development of kindled convulsions. The data indicate that the development of kindled convulsions was directly proportional and cumulative with repeated exposure to PTZ. Fig. 2A and B illustrate the effects of pretreatment with quinolone derivatives on the development of kindled convulsions (phase 4, appearance of hind limb clonus and fore limb tonus). Ciprox, peflox, oflox, M5 and MH5 derivatives increased the development of kindling to PTZ induced seizures during the 6 weeks of treatment, whilst cinox and nalidix did not significantly
Fig. 1. (A) Development of kindling to PTZ (30 mg/g, s.c.). Effects of the repeated administration of vehicle, peflox, oflox, cinox and MH5 derivative (20 mg/g, i.p. 15 min before PTZ) on the manifestation of kindling during once every 2 days treatment with PTZ (30 mg/g, s.c.). Ordinate shows the seizure score, abscissa shows the weeks of repeated treatment. (B) Development of kindling to PTZ (30 mg/g, s.c.). Effects of the repeated administration of vehicle, ciprox, nalidix, and M5 derivative (20 mg/g, i.p. 15 min before PTZ) on the manifestation of kindling during treatment once every 2 days with PTZ (30 mg/g, s.c.). Ordinate shows the seizure score, abscissa shows the weeks of repeated treatment.
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mechanism of kindling or even whether electrical and chemical kindling share common mechanisms [18,21]. Many studies suggest that the increased susceptibility associated with kindling may involve either a decrease in the functional properties of the GABA system or an increase in the functional properties of the glutamate system and there is evidence that glutamate antagonists retard the development of kindling [19,22–26]. Recent studies of Rocha and coworkers [27,28] show that PTZ-induced kindling may be associated with significant changes of the GABAergic system and benzodiazepine binding and with an imbalance between excitatory and inhibitory systems early in the epileptogenic process. In particular, as outlined by Mody and Heinemann [24] the activation of excitatory amino acid (EAA) receptor mediated excitation induced by kindling may involve: (1) progressive activation of dormant EAA receptors, (2) increase in the number of EAA receptors, (3) structural alterations resulting in enhanced exposure of EAA receptors to the neurotransmitters and (4) enhanced neurotransmitter release. Thus, both changes
Fig. 2. (A) and (B) Percentage of convulsing mice (phase 4) at 21, 28, 35 and 42 days of treatment (vehicle + PTZ or quinolones+ PTZ). Ordinate shows the percentage of mice showing at least phase 4, abscissa shows the days of repeated treatment.
dled status persisted in some animals for at least 30 days reflecting a relatively long-term change in excitability of CNS.
4. Discussion This study was performed as part of a continuing series of investigations on the epileptogenic facilitating properties of quinolone derivatives. Although a variety of studies regarding the CNS effects of quinolones have already been conducted, the mechanism of the ability of quinolones to facilitate epileptogenic activity is largely unresolved [7,8,20]. Recent studies demonstrated that some quinolones have different potentials for potentiating the convulsant effects of PTZ [12,13]. In the present study we used the kindling model of epilepsy because this model offers the possibility of differentiating between acute and kindling-related effects of convulsant drugs. Kindling is a chronic model of epilepsy and it is of considerable interest that this experimental model is more closely related to human epilepsy than acute chemoconvulsant or electrical models [19]. The kindling phenomenon has been described in many animal species but little is understood about the
Fig. 3. (A) and (B) Effects of challenge with PTZ on mice receiving vehicle + PTZ or some quinolone+PTZ for 6 weeks. (A) Animals were challenged with PTZ (25 mg/kg, s.c.) 15 days after the completion of the chronic treatment and the occurrence of clonic seizures were observed.
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Fig. 4. Effects of challenge with PTZ on mice repeatedly receiving vehicle, vehicle+PTZ or oflox+ PTZ, ciprox+PTZ, peflox+ PTZ and MH5 derivative+ PTZ for 6 weeks. The animals were challenged with PTZ (25 mg/kg, s.c.) 30 days after the completion of the chronic treatment and the occurrence of clonic seizures were observed.
at the level of EAA and/or GABA receptors and downstream from these receptors, e.g. a level of other neurotrasmitter systems, which are under glutamatergic or GABAergic influence, may be involved in the chemical kindling induced epileptogenesis. In addition, recent studies indicate that PTZ kindling enhances hippocampal acetylcholine release and sensitivity of dopamine neurons in the rat brain to PTZ suggesting that cholinergic and dopaminergic system may also contribute to the central alterations associated with this model of experimental epilepsy [29,30]. In this study we demonstrated that quinolones have different abilities to potentiate the development of kindling caused by repeated exposure to PTZ and that kindling effects persist for several days as illustrated by the withdrawal data (Fig. 3A and B, Fig. 4). In fact, such enhanced sensitivity of PTZ-kindled mice pretreated with some quinolones was still observed both 15 and 30 days after the last kindled seizure, confirming a long-lasting, if not permanent, hypersensitivity associated with this experimental model of epilepsy. Like PTZ, quinolones also block the actions of GABA through its effects at the chloride ionophore coupled to the BDZ-GABAA receptor complex [8,11]. Thus the enhanced kindling development observed after the combined administration of quinolones and PTZ in mice, might be mediated through synergistic inhibitory effects on GABA transmission. This hypothesis is consistent with data showing that GABA agonists antagonize both PTZ and quinolones induced seizures [8,27,28,31]. However, the concentration needed for an interaction between a quinolone and the GABA receptor is rather high and varied with different quinolones tested by a factor of approximately 100. Thus, it appears questionable that a specific interaction of quinolones with the GABA receptor can be the only explanation of the
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proconvulsant activity of these compounds [32]. Indeed, in contrast to the GABAergic mechanism, some authors suggested that other receptors may also be involved in the CNS effects of quinolones, such as opioid and excitatory amino acid receptors [31,33–35]. Therefore, a GABAergic mechanism is thought to be an essential, but not the sole component of the mechanism by which quinolones induce seizures; glutamate is also suspected of being involved [31,34]. Recent studies have clearly shown that compounds which antagonize ionotropic glutamate receptors inhibit quinolone-induced seizures in mice and therefore we suggest that it is most likely that excessive activation of glutamate receptors occurs secondarily to or concomitantly with the impairment of the inhibitory GABAergic neurotransmission caused by quinolones and it is essential for both the propagation of seizures and the development of kindling [31,33,34]. The present study supported and extended previous observations that some quinolones potentiate the convulsant effects of PTZ [12,13]. The finding that some quinolone derivatives potentiate the kindling status induced by chronic treatment with subconvulsant doses of PTZ could be related to structural synaptic alterations associated with the kindling, which involve either a decrease in the functional properties of GABA system and/or an increase in the functional properties of the glutamate system [24,26,36]. The experimental approach described in this article could be used to evaluate the potential of new quinolone derivatives to induce seizures, thus making it possible to select compounds with a reduced risk of causing convulsions in the clinical setting.
Acknowledgements This research was supported by the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (MURST 60%). A preliminary account of these findings has been presented at EEC-2 10–13 May 1998, in Hamburg, Germany.
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