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Histamine is one of the aminergic neurotransmitters, playing an important role in the regulation of a number of physiological processes. There are several subtypes of histamine receptors-H(1), H(2), H(3) and the recently discovered H(4). H(1) receptors exist on mast cells, basophils, enterochromaffin cells and in the central nervous system, being located postsynaptically. H(1) receptor antagonists, including classical antiallergy drugs, occasionally have been expected to induce convulsions in children and epileptics. The aim of this study was to evaluate the effects of astemizole-given intraperitoneally, singly or for 7 days on the anticonvulsant activity of antiepileptic drugs (AEDs) against maximal electroshock (MES)-induced convulsions in mice. The following AEDs were administered intraperitoneally: valproate magnesium, carbamazepine, diphenylhydantoin and phenobarbital. Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of AEDs were measured by immunofluorescence. Astemizole (a single dose and following a 7-day treatment at 2-6 mg/kg) reduced the threshold for electroconvulsions, being without effect upon this parameter at lower doses. Astemizole (1 mg/kg) did not significantly alter the protective effect of AEDs against MES (after acute and 7-day administration). Also, acute astemizole (2 mg/kg) remained ineffective in this respect. Astemizole (2 mg/kg), following chronic administration, significantly reduced the protective efficacy of phenobarbital and diphenylhydantoin, reflected by an increase in their ED(50) values (50% effective dose necessary to protect 50% of animals tested against MES) from 21.1 to 34.0 mg/kg and from 10.4 to 19.2 mg/kg, respectively. Astemizole (2 mg/kg) did not alter the protective activity of the remaining AEDs. Moreover, astemizole (2 mg/kg) did not influence the free plasma levels and brain concentration of the studied AEDs. Also, this H(1) receptor antagonist did not impair long-term memory or motor coordination when given acutely. However, 7-day treatment with astemizole (2 mg/kg) significantly decreased TD(50) (50% toxic dose required to induce motor impairment in 50% of animals) value of phenobarbital, being without effect on carbamazepine, valproate and diphenylhydantoin in this respect. Similarly, phenobarbital and diphenylhydantoin, administered alone at their ED(50)s against MES, or combined with astemizole, disturbed long-term memory in mice. The results of this study indicate that astemizole may need to be used with caution in epileptic patients.

The aim of this study was to evaluate effects of strychnine, as well as bicuculline and picrotoxin on the anticonvulsant action of felbamate against maximal electroshock (MES)-induced seizures in mice. Strychnine (up to 0.5 mg/kg), bicuculline (up to 2 mg/kg) and picrotoxin (3 mg/kg) did not affect the seizure threshold. However, strychnine (0.25-0.5 mg/kg) and picrotoxin (3 mg/kg) impaired the protective activity of felbamate against MES. It may be concluded that GABAergic inhibition and strychnine-insensitive glycine receptor-mediated events may contribute to the anticonvulsant activity of felbamate.

Experimental data indicate that nitric oxide (NO) may play a role in the pathophysiology of epilepsy. It is also possible that NO-mediated events are involved in the expression of the anticonvulsant action of some antiepileptics. The aim of this review was to assemble current literature data on the role of NO in the anticonvulsant action of antiepileptic drugs (AEDs). The influence of various NO synthase inhibitors (NOSI) on antiseizure activity of AEDs was tested in many animal experimental models of epilepsy (electrically and pharmacologically evoked seizures, sound-induced convulsions, amygdala-kindled seizures). Although some NOSI were able to modify the anticonvulsive properties of AEDs, the involvement of NO pathway in the mechanisms of action of AEDs in most cases does not seem probable, since the effects of NOSI were not reversed by L-arginine, a NO precursor.

Tiagabine (TGB), a new potent gamma-aminobutyric acid (GABA) uptake inhibitor, is widely applied in adjunctive treatment of partial seizures in humans. Although, polytherapy is not an initial method of epilepsy treatment, clinicians often combine TGB with other antiepileptics as add-on therapy for assuring the anticonvulsant protection in patients with refractory seizures. To evaluate the character of pharmacological interactions between TGB and some antiepileptics, the isobolographic analysis was used as a suitable method for determining the exact types of interactions. Determination of an influence of TGB on the protective effects of diphenylhydantoin (DPH), carbamazepine (CBZ), valproate (VPA), phenobarbital (PB), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) in maximal electroshock-induced seizures was essential for this study. To exclude or confirm a pharmacokinetic character of observed interactions, the free plasma and brain concentrations of antiepileptic drugs (AEDs) studied were evaluated by using the immunofluorescence or high-pressure liquid chromatography (HPLC).TGB (up to 2.5 mg/kg) remained ineffective upon the electroconvulsive threshold, whilst the drug in doses of 5 and 10 mg/kg significantly raised the electroconvulsive threshold in mice. According to the isobolography, TGB appears to act synergistically with VPA. The remaining combinations tested exerted additive interactions. A pharmacokinetic character of interaction between TGB and VPA was evidently corroborated either in plasma or brains. Moreover, TGB significantly reduced the plasma and brain concentrations of DPH; however, pharmacokinetic events were not accompanied by any changes in anticonvulsant activity of the latter. Finally, the isobolographic analysis revealed that combinations of TGB with VPA exerted synergistic (supra-additive) interaction resulting from a pharmacokinetic interaction.

Vigabatrin is a novel antiepileptic drug, which increases GABA levels by irreversible inhibition of GABA-aminotransferase. The aim of this study was to evaluate the effects of vigabatrin on the anticonvulsant activity of valproate, ethosuximide and clonazepam against pentetrazole-induced seizures in mice. In addition, the effects of antiepileptic drugs alone or in combination with vigabatrin were studied on motor performance and long-term memory. Chemical seizures were induced by subcutaneous injection of pentetrazole at its CD(97) and defined as a clonus of the whole body with an accompanying loss of righting reflex, lasting for over 3 s. Vigabatrin inhibited the clonic pentetrazole-induced seizures and ED(30) of the drug was 879 mg/kg. Vigabatrin (at the subthreshold dose of 250 mg/kg) potentiated the protective activity of ethosuximide, reducing its ED(30) from 142 to 95 mg/kg against clonic seizures induced by pentetrazole, but simultaneously elevated its plasma level. The protective activity of valproate and clonazepam remained almost unchanged. However, vigabatrin (250 mg/kg) decreased TD(30) (50% toxic dose - corresponding to the impairment of motor coordination in 50% of the animals) of ethosuximide and clonazepam from 549 and 3.84 to 460 and 1.1 mg/kg, respectively, in the chimney test. Vigabatrin (250 mg/kg) did not influence TD(30) value of valproate in this test. Vigabatrin (at the dose of 250 mg/kg) did not impair long-term memory in combination with antiepileptics. Potentiation of the ethosuximide's protective activity was apparently due to a pharmacokinetic interaction. Consequently, no pharmacodynamic interactions between vigabatrin and the studied conventional antiepileptic drugs were evident.

LY 300164 [7-acetyl-3-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxazolo[4,5-h][2,3]-benzodiazepine], a novel AMPA/kainate receptor antagonist, administered intraperitoneally protected mice against aminophylline-induced seizures. At doses up to 0.5 mg/kg, which did not significantly affect the convulsant activity of aminophylline, it potentiated the protective activity of diazepam. On the other hand, LY 300164 used at the lowest protective dose of 1.0 mg/kg enhanced anticonvulsant activity of all antiepileptic drugs tested in this seizure model. However, LY 300164 neither alone nor combined with antiepileptic drugs, reduced aminophylline-induced mortality.

Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising.

SIB 1893, a non-competitive antagonist of group I metabotropic glutamate receptor subtype 5, administered at the doses ranging between 0.5-2 mg/kg markedly lowered the electroconvulsive threshold, whereas if applied at the higher dose of 40 mg/kg, it significantly raised the threshold for electroconvulsions in mice, exhibiting both pro- and anticonvulsive properties in this test.

The objective of this study was to determine whether electroconvulsions lead to excessive lipid peroxidation. The concentrations of the conjugated dienes (CD) and malonyl dialdehyde (MDA) in the homogenates of the brains after seizures induced with 25 mA current (MES) measured immediately after seizures were significantly higher in comparison with the control brains. There were no significant differences between control group and animals treated with multiple MES. Significant rise in CD concentrations was also observed at 1 h following MES. The results indicate that electroconvulsions may lead to the increased formation of lipid peroxidation products.

A number of neurosteroids exert antiseizure and/or neuroprotective properties. The aim of this study was to evaluate the effect of the neurosteroid alphaxalone on the protective action of conventional antiepileptics in four seizure tests. Alphaxalone (up to 5 mg/kg) did not exert a significant action against amygdala-kindled seizures in rats, or against pentetrazole- or aminophylline-induced convulsions in mice. The neuroactive steroid at the dose of 2.5 mg/kg significantly raised the threshold for electroconvulsions in mice. At 2.5 mg/kg, alphaxalone diminished the protective activity of valproate against maximal electroshock and at 2.5-5 mg/kg against pentetrazole-induced seizures in mice. However, alphaxalone (2.5 mg/kg) did not affect the protective activity of carbamazepine, diphenylhydantoin, phenobarbital or clonazepam against maximal electroshock and at 5 mg/kg did not affect that of phenobarbital, clonazepam and ethosuximide against pentetrazole-induced convulsions. Insignificant results were also obtained in the case of co-administration of alphaxalone with phenobarbital, valproate, clonazepam and carbamazepine against aminophylline-evoked seizures in mice. Also, in the kindling model of epilepsy, combinations of the neuroactive steroid (2.5 mg/kg) with valproate, carbamazepine, phenobarbital, diphenylhydantoin or clonazepam at their subprotective doses did not result in pro- or anticonvulsant activity. Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice. Alphaxalone (2.5 mg/kg), valproate (at its ED(50) value of 226 mg/kg) and the combination of valproate (284 mg/kg) with alphaxalone (2.5 mg/kg) did not affect long-term memory, evaluated in the passive avoidance task with mice. Alphaxalone administered alone or in combination with valproate caused no motor impairment in experimental animals. Finally, alphaxalone (2.5 and 5 mg/kg) significantly increased the free plasma levels of valproate, strongly indicating that the neuroactive steroid-induced reduction of the protective activity of valproate is not related to pharmacokinetic phenomena. Summing up, alphaxalone does not seem to be a promising candidate for adjunctive treatment of epilepsy.

The influence of molsidomine, a donor of nitric oxide (NO), L-arginine, a substrate for NO synthesis, and N(G)-nitro-L-arginine (NNA), an inhibitor of NO synthase, on the protective activity of CGP 40116, GYKI 52466, MK-801, and riluzole against electroconvulsions was studied in mice. Molsidomine (100 mg kg(-1); i.p.) potentiated the protective activity of GYKI 52466, MK-801, and riluzole but did not influence the protection offered by CGP 40116. In contrast to molsidomine, L-arginine (500 mg kg(-1); i.p.) did not impair the protective activity of any anticonvulsant. In a dose of 40 mg kg(-1), NNA administered i.p. did not affect the protection offered by any excitatory amino acid antagonists and riluzole. Combinations of molsidomine with either GYKI 52466 or MK-801 as well as riluzole did not cause a memory deficit in the passive avoidance task. However, the combined treatment of molsidomine with these anticonvulsants resulted in a motor impairment quantified by the chimney test. The lack of effect of L-arginine and NNA on the protective activity of excitatory amino acid antagonists suggests that molsidomine-evoked alterations in the protection provided by some excitatory amino acid antagonists against electroconvulsions are independent of the NO pathway.

It was previously documented that calcium (Ca(2+)) channel inhibitors intensified the protective effects of conventional antiepileptics against electroconvulsions in mice. The aim of this study was to evaluate the effects of Ca(2+) channel inhibitors (nifedipine, nicardipine and flunarizine) on the anticonvulsant action of the new AMPA/kainate receptor antagonist, 7-acetyl-3-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxazolo[4,5-h][2,3]-benzodiazepine (LY 300164), against maximal electroshock (MES)-induced seizures in mice. Dantrolene (an inhibitor of Ca(2+)release from intracellular stores) was also included. Nifedipine (30 mg/kg) and flunarizine (15 mg/kg) raised the threshold for electroconvulsions, being ineffective at lower doses. Nicardipine (up to 30 mg/kg) and dantrolene (up to 20 mg/kg) did not affect this parameter. Flunarizine (10 mg/kg), nicardipine (20 mg/kg) and dantrolene (20 mg/kg) potentiated the efficacy of LY 300164 against MES. However, nicardipine (at 20 mg/kg) raised the free plasma concentration of LY 300164. Nifedipine (30 mg/kg), given even in a dose raising the electroconvulsive threshold, did not significantly alter the protective effect of LY 300164 against MES. Furthermore, the Ca(2+) channel agonist-BAY k-8644 (at 5 mg/kg) did not influence the protection offered by LY 300164 against MES. Finally, this Ca(2+) channel activator did not affect the enhanced efficacy of LY 300164 by Ca(2+) channel modulators. The only exception was the combination of LY 300164 with flunarizine. Combined treatment with LY 300164 and dantrolene (20 mg/kg), compared to LY 300164 alone, resulted in an impairment of motor performance in mice. Ca(2+) channel inhibitors were without effect upon this parameter evaluated in the chimney test. As shown in the passive avoidance task, LY 300164 alone (at its ED(50)) or combined with agents affecting neuronal Ca(2+) concentration did not disturb long-term memory. The present results suggest that agents preventing influx of Ca(2+) ions into neurons may enhance the protective action of LY 300164.

2-Chloroadenosine (0.25-1 mg/kg) significantly raised the threshold for electroconvulsions in mice. This preferential adenosine A(1) receptor agonist (at 0.125 mg/kg) significantly potentiated the protective activity of carbamazepine against maximal electroshock-induced seizures in mice. 2-Chloroadenosine (1 mg/kg) showed also anticonvulsive efficacy against pentylenetetrazol-evoked seizures, raising the CD(50) value for pentylenetetrazol from 77.2 to 93.7 mg/kg. The drug (at 0.5 mg/kg) significantly enhanced the protective action of clonazepam in this test, decreasing its ED(50) value from 0.033 to 0.011 mg/kg. Moreover, aminophylline, a non-selective adenosine receptor antagonist (5 mg/kg), and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX), a selective A(1) adenosine receptor antagonist (5 mg/kg) reversed the 2-chloroadenosine (0.125 mg/kg)-induced enhancement of the protective activity of carbamazepine and clonazepam. 2-Chloroadenosine administered alone or combined with antiepileptic drugs, caused neither motor nor long-term memory impairment. Finally, the adenosine A(1) agonist did not change the free plasma concentration of antiepileptics, so a pharmacokinetic factor is not probable. Summing up, 2-chloroadenosine potentiated the protective activity of both carbamazepine and clonazepam, which seems to be associated with the enhancement of purinergic transmission mediated through adenosine A(1) receptors.

The aim of this study was to evaluate the efficacy of three antihormones, tamoxifen (TXF, an antiestrogen), mifepristone (MIF, an antiprogesterone) and cyproterone (CYP, an antiandrogen) in two major models of experimental epilepsy, electrically and pentetrazole (PTZ)-evoked seizures in mice. TXF (20-50 mg/kg) significantly raised the threshold for electroconvulsions in female mice, whereas CYP was active in male mice. Similar effects were observed in castrated mice. Different data were obtained in sexually immature animals since both TXF and CYP exerted anticonvulsive effects in animals of both genders. MIF (5-50 mg/kg) remained without effect on electrically evoked seizures in mice. The anticonvulsive action of TXF was reversed by aminophylline, bicuculline, kainic acid and N-methyl-D-aspartic acid, but not by estradiol or strychnine. The protective action of CYP was reversed by aminophylline and bicuculline, but not by testosterone, kainic acid, N-methyl-D-aspartic acid or strychnine. All three antihormones were ineffective against PTZ-induced convulsions in mice. Our results suggest that the action of TXF and CYP might be indirectly associated with the respective hormonal receptor-mediated events, but the nature of this dependence is unclear and further investigations are needed to elucidate this phenomenon.

We studied whether N(G)-nitro-L-arginine (NNA), an inhibitor of nitric oxide (NO) synthase as well as L-arginine and molsidomine, two agents elevating NO, influenced convulsions caused by 4-aminopyridine, a K+ channel blocker in mice. NNA, in a dose known to decrease level of NO (40 mg x kg(-1)), enhanced the seizure susceptibility to intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) 4-aminopyridine. L-arginine (500 mg x kg(-1)) and molsidomine (20 mg x kg(-1)) alone did not influence 4-aminopyridine-induced seizure activity. Surprisingly, the proconvulsant effect of NNA upon clonic and tonic seizures was potentiated by molsidomine (20 mg x kg(-1)). No influence of L-arginine on the proconvulsant effect of NNA was found. Taking into account the proconvulsant effect of NNA, an involvement of NO-mediated events in the mechanism of convulsive activity of 4-aminopyridine might be postulated. However, the ineffectiveness of L-arginine and molsidomine to suppress the convulsive activity of 4-aminopyridine as well as a paradoxical potentiation of the proconvulsant effect of NNA by molsidomine seem to exclude the impact of NO pathway on 4-aminopyridine-induced convulsions in mice. Our data suggest that the proconvulsant effect of NNA in this seizure model is caused by other, not related to NO, mechanisms.

The anticonvulsive potential of classical antiepileptics co-administered with beta-adrenergic receptor antagonists against generalized tonic-clonic seizures was evaluated in the model of maximal electroshock (MES)-induced convulsions. Propranolol, acebutolol, metoprolol and atenolol were tested in the doses not affecting the electroconvulsive threshold. Propranolol and metoprolol lowered the ED(50) of valproate and diazepam. Acebutolol reduced valproate's but not diazepam's ED(50) value. In contrast, hydrophilic atenolol, not penetrating via blood-brain barrier, affected neither the action of valproate nor diazepam. None of the studied drugs changed the protective activity of carbamazepine and phenytoin against MES. beta-blockers per se did not alter the motor performance of mice. Moreover, propranolol and metoprolol did not influence diazepam-evoked impairment of locomotor activity. The free plasma and brain levels of antiepileptic drugs were not affected by beta-blockers. In conclusion, the use of certain beta-adrenoceptor antagonists, such as propranolol and metoprolol, might improve the antiepileptic potential of valproate and diazepam.