Correction to: Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

The article Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

BACKGROUND: The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice. METHODS: VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured. RESULTS: After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration. CONCLUSIONS: The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.

Assessment of the anticonvulsant potency of various benzylamide derivatives in the mouse maximal electroshock-induced seizure threshold model.

PURPOSE: The aim of this study was to assess the anticonvulsant potency of 6 various benzylamide derivatives [i.e., nicotinic acid benzylamide (Nic-BZA), picolinic acid 2-fluoro-benzylamide (2F-Pic-BZA), picolinic acid benzylamide (Pic-BZA), (RS)-methyl-alanine-benzylamide (Me-Ala-BZA), isonicotinic acid benzylamide (Iso-Nic-BZA), and (R)-N-methyl-proline-benzylamide (Me-Pro-BZA)] in the threshold for maximal electroshock (MEST)-induced seizures in mice. METHODS: Electroconvulsions (seizure activity) were produced in mice by means of a current (sine-wave, 50Hz, 500V, strength from 4 to 18mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). RESULTS: Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA administered systemically (ip) in a dose-dependent manner increase the threshold for maximal electroconvulsions in mice. Linear regression analysis of Nic-BZA, 2F-Pic-BZA, Pic-BZA, MeAla-BZA, IsoNic-BZA, and Me-Pro-BZA doses and their corresponding threshold increases allowed determining threshold increasing doses by 20% (TID20 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 values in the MEST test for Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA were 7.45mg/kg, 7.72mg/kg, 8.74mg/kg, 15.11mg/kg, 21.95mg/kg and 28.06mg/kg, respectively. CONCLUSION: The studied benzylamide derivatives can be arranged with respect to their anticonvulsant potency in the MEST test as follows: Nic-BZA>2F-Pic-BZA>Pic-BZA>Me-Ala-BZA>Iso-Nic-BZA>Me-Pro-BZA.

The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice.

PURPOSE: The aim of this study was to evaluate the effects of 1-day, 7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, phenytoin and phenobarbital) against maximal electroshock (MES)-induced convulsions in mice. METHODS: Electroconvulsions were evoked in Albino Swiss mice by a current delivered via ear-clip electrodes. In addition, the effects of cimetidine, AEDs alone and their combinations were studied on performance and long-term memory tests. Pharmacokinetic changes in plasma and brain concentrations of AEDs after cimetidine administration were evaluated with immunofluorescence. RESULTS: Cimetidine (up to 100mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. Moreover, in the 14-day treatment, cimetidine administered at a dose of 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/kg) significantly increased the anticonvulsant activity of carbamazepine, staying without effects after a 1-day and 7-day studies. In contrast, both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. Only valproate and phenytoin were not affected by cimetidine (20mg/kg) in all experimental period. Cimetidine administered 1-day, did not alter total brain concentrations and free plasma levels of all AEDs tested, whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. Cimetidine co-applied with AEDs did not impair performance of mice evaluated in the chimney test however, it worsened long-term memory in animals. CONCLUSIONS: Based on this preclinical study, a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine.

Protective action of nicotinic acid benzylamide in a variety of chemically-induced seizures in mice.

PURPOSE: The study aims to assess the anticonvulsant effects offered by benzylamide nicotinic acid (Nic-BZA) in many animal models of chemically-induced seizures (i.e., pentylenetetrazole [PTZ], pilocarpine [PILO], bicuculline [BIC], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], kainic acid [KA], and N-methyl-d-aspartic acid [NMDA]). Additionally, it analyses side effects of administering Nic-BZA in the form of loss of co-ordination and memory impairment as evaluated in the rotarod and passive avoidance tests, respectively. RESULTS: Antiseizure activity of Nic-BZA was reported in numerous models of chemically-induced seizures and its ED50 value was 37.1mg/kg for PTZ, 53.0mg/kg for AMPA, 81.4mg/kg for BIC, 86.3mg/kg for KA, and 182.6mg/kg for PILO. Moreover, Nic-BZA was totally ineffective (in dosages of up to 200mg/kg) in mice challenged with NMDA-induced seizures. The evaluation of the side effects present shortly after dosing in the rotarod test has revealed neurotoxicity of Nic-BZA with experimentally determined TD50 value of 188.5mg/kg. Protective index (PI) assessment analysis for Nic-BZA has disclosed a substantial difference between the dosage resulting in acute impairment of co-ordination and the dosage resulting in anticonvulsant effect in various chemically evoked seizures, remaining practically ineffective (in dosages of up to 200mg/kg) in mice subjected to the NMDA-induced seizure test. Additionally, Nic-BZA (in dosages of up to 100mg/kg) did not impair long-term memory in mice. CONCLUSIONS: Summing up, Nic-BZA has a wide anticonvulsant effect in different experimental epilepsy models.

Modulation of adenosinergic system and its application for the treatment of epilepsy.

Adenosine is present in all cells and is implicated in the control of the function of every tissue and organ. The elevated adenosine levels seem to play a significant role in a protection against cellular damage in the regions with increased metabolic demand and prevent the subsequent dysfunction of the affected organs. Furthermore, adenosine has been shown to play an important role not only in the regulation of pathophysiological processes, but also in the modulation of normal physiological processes, for example, the regulation of sleep and arousal as well as by impact on pre- or postsynaptic receptors involved in releasing neurotransmitters (e.g. glutamate, acetylcholine, norepinephrine, 5-hydroxytryptamine, dopamine, GABA and others). Experimental studies provide evidence supporting the role of adenosine as an endogenous anticonvulsant agent. Numerous adenosine agonists acting through A1, A2 and A3 receptors were proven as potent anticonvulsant compounds in a wide variety of animal models of epilepsy. However, despite their efficacy in such models, adenosine receptor agonists do not appear to be good candidates for successful clinical applications. The therapeutic range of systemically administered adenosine receptor agonists is very narrow and they often produce profound adverse events. It seems, therefore, that adenosine receptor agonists could only be used clinically when co-administered with other antiepileptic drugs or when used in local therapies, where their side effect profile is much more tolerable. An alternative strategy would be to enhance the natural adenosinergic feedback mechanism triggered by seizures by using adenosine uptake inhibitors. This approach seems very attractive as it would allow limiting the action only in the active areas such as seizure foci and thus, preventing the systemic side effects.

Interaction of famotidine, an H2 histamine receptor antagonist, with conventional antiepileptic drugs in mice.

H2 histamine receptors are localized postsynaptically in the CNS. The aim of this study was to evaluate the effects of acute (1 day) and prolonged (7 day) administration of the H2 histamine receptor antagonist, famotidine, on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock (MES)-induced seizures in mice. In addition, the effects of these drugs alone or in combination with famotidine were studied on motor performance and long-term memory. The influence of H2 receptor antagonist on brain concentrations and free plasma levels of the antiepileptic drugs was also evaluated. After acute or prolonged administration of famotidine (at dose of 10mg/kg) the drug raised the threshold for electroconvulsions. No effect was observed on this parameter at lower doses. Famotidine (5mg/kg), given acutely, significantly enhanced the anticonvulsant activity of valproate, which was expressed by a decrease in ED50. After the 7-day treatment, famotidine (5mg/kg) increased the anticonvulsant activity of diphenylhydantoin against MES. Famotidine (5mg/kg), after acute and prolonged administration, combined with valproate, phenobarbital, diphenylhydantoin and carbamazepine did not alter their free plasma levels. In contrast, brain concentrations of valproate were elevated for 1-day treatment with famotidine (5mg/kg). Moreover, famotidine co-applied with AEDs, given prolonged, worsened motor coordination in mice treated with carbamazepine or diphenylhydantoin. In contrast this histamine antagonist, did not impair the performance of mice evaluated in the long-term memory task. The results of this study indicate that famotidine modifies the anticonvulsant activity of some antiepileptic drugs.

Anticonvulsant and acute adverse effect profiles of picolinic acid 2-fluoro-benzylamide in various experimental seizure models and chimney test in mice.

The objective of this study was to evaluate the anticonvulsant properties of picolinic acid 2-fluoro-benzylamide (Pic-2F-BZA) in numerous experimental seizure models [maximal electroshock (MES), bicuculline (BIC), pentylenetetrazole (PTZ), pilocarpine (PILO), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA) and N-methyl-D-aspartic acid (NMDA)-induced seizures]. Moreover, the acute adverse-effect profile of the agent with respect to impairment of motor performance was assessed in animals subjected to the chimney test. Results indicate that Pic-2F-BZA in time- and dose-dependent manners produced both the anti-electroshock action and acute adverse effects in the MES and chimney tests in mice respectively. The experimentally derived median effective dose (ED(50) value) in the MES test was 24.2 mg/kg (at 5 min after i.p. administration), whereas the median toxic dose (TD(50) value) in the chimney test was 71.7 mg/kg. Furthermore, Pic-2F-BZA produced clear-cut antiseizure effects in all chemically induced seizure models and its ED(50) values amounted to 19.9 mg/kg for KA-, 39.5 mg/kg for AMPA-, 56.2 mg/kg for PTZ-, 76.4 mg/kg for BIC-, 160.1 mg/kg for PILO- and 165.2 mg/kg for NMDA-induced seizures. Based on this study, one can conclude that Pic-2F-BZA, because of its broad spectrum of anticonvulsant action and the short time to peak of its maximum anticonvulsant effects (5 min after its i.p. administration), deserves more attention as a potential antiepileptic drug for status epilepticus patients.

Characterization of the anticonvulsant profile of isonicotinic acid benzylamide in various experimental seizure models in mice.

This study focused on the evaluation of anticonvulsant properties of isonicotinic acid benzylamide (iso-Nic-BZA) in numerous experimental seizure models (maximal electroshock [MES]-, bicuculline [BIC]-, pentylenetetrazole [PTZ]-, pilocarpine [PILO]-, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]-, kainic acid [KA]- and N-methyl-d-aspartic acid [NMDA]-induced seizures). Moreover, acute adverse-effect profile of the agent with respect to impairment of motor coordination was assessed in animals subjected to the chimney test. The evaluation of time-course and dose-response relationships for iso-Nic-BZA provided evidence that the compound produced the peak to maximum antielectroshock action and acute adverse effects at 5min after its systemic (i.p.) administration. Iso-Nic-BZA exerted a clear-cut anticonvulsant action against maximal electroshock-induced seizures in mice and its ED(50) value was 70.6 (56.4-88.4)mg/kg. The assessment of acute adverse effects in the chimney test revealed that the agent produced acute neurotoxic effects and its TD(50) value was 135.6 (108.8-169.0)mg/kg. Additionally, iso-Nic-BZA showed the anticonvulsant activity in numerous chemically-induced seizures (AMPA-, BIC-, KA-, and PTZ-evoked clonic convulsions), remaining virtually ineffective (at doses up to 200mg/kg) in PILO- and NMDA-induced seizures in mice. Based on this study, one can conclude that iso-Nic-BZA due to the short time to peak of its maximum anticonvulsant effects (5min after its i.p. administration), deserves more attention as a potential antiepileptic drug for patients in status epilepticus.

Anticonvulsant and acute neurotoxic characteristics of nicotinic acid benzylamide: a preclinical study.

The aim of this study was to evaluate time-course and dose-response relationships of nicotinic acid benzylamide (Nic-BZA) with regard to its anticonvulsant activity in the maximal electroshock (MES)-induced seizures and acute neurotoxic effects in terms of motor coordination impairment in the chimney test in mice. The experimental determination of both median effective dose (ED(50)) and median toxic dose (TD(50)) allowed for the calculation of protective index (PI) values characterizing a preclinical profile of Nic-BZA. Results indicated that Nic-BZA produced the time-dependent and clear-cut anticonvulsant activity in the MES test and its ED(50) values ranged between 35.7 and 84.0 mg/kg (after the ip administration of the agent at 5 and 60 min, respectively), and between 72.0 and 152.1 mg/kg (at 5 and 60 min, respectively, following the po administration of Nic-BZA). In the chimney test, the TD(50) values for Nic-BZA, after its ip administration ranged between 188.5 and 509.9 mg/kg, whereas following its po administration the TD(50) values for Nic-BZA were between 552 and 1222.1 mg/kg. The PI values for Nic-BZA, calculated at various times after its ip and po administrations (ranging between 3.56 and 17), revealed that the agent has a favorable profile, when considering its both anticonvulsant and acute neurotoxic effects in this preclinical study. Based on this study, one can conclude that Nic-BZA might occur advantageous as a potential antiepileptic drug for breaking seizure attacks in patients with epilepsy.

Influence of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs against pentetrazole-induced seizures in mice.

The aim of this study was to evaluate the effects of acute (1 day) and chronic (7 days) administrations of cimetidine, an H2 histamine receptor antagonist, on the protective activity of conventional antiepileptic drugs (AEDs) against pentetrazole (PTZ)-induced seizures in mice. Cimetidine (up to 100 mg/kg), given alone either acutely or chronically, did not alter significantly PTZ-induced seizures in mice. However, the drug (at 20 mg/kg, administered acutely) potentiated the anticonvulsant activity of ethosuximide (ETX) by reducing its ED50 from 134 to 103 mg/kg (p < 0.05). This effect was associated with a 74% elevation of plasma ETX level (p < 0.01). In contrast, chronic (7 days) administration of cimetidine (20 mg/kg) did not affect the anticonvulsant activity of ETX in the PTZ test and its plasma levels. On the other hand, cimetidine (20 mg/kg), given either acutely or chronically, when co-administered with valproate, clonazepam, and phenobarbital had no significant impact on the anticonvulsant properties of these AEDs against PTZ-induced seizures and their plasma levels in mice. The results indicate that there may be no risk in prescribing cimetidine for other than epilepsy reasons in patients treated with valproate, clonazepam or phenobarbital.

2-Chloro-N6-cyclopentyladenosine enhances the anticonvulsant action of carbamazepine in the mouse maximal electroshock-induced seizure model.

This study examines the anticonvulsant profile of interactions between 2-chloro-N6-cyclopentyladenosine (CCPA, a selective adenosine A1 receptor agonist) and four conventional antiepileptic drugs (AEDs: carbamazepine--CBZ, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure (MES) model. Acute adverse effects produced by AEDs in combination with CCPA were determined in the chimney test (motor performance) and passive avoidance task (long-term memory). Results indicate that CCPA administered alone at 0.25 and 0.5 mg/kg significantly elevated the electroconvulsive threshold in mice. Additionally, the agent at a sub-threshold dose of 0.125 mg/kg potentiated the anticonvulsant activity of CBZ by reducing its ED50 in the MES test from 11.2 to 7.7 mg/kg (p < 0.01). In contrast, 8-cyclopentyl-1,3-dimethylxanthine (DPCPX, a selective adenosine A1 receptor antagonist at 5 mg/kg) abolished the enhanced anticonvulsant effects offered by the combination of CBZ with CCPA (0.125 mg/kg). Moreover, CCPA (0.125 mg/kg) co-administered with other tested AEDs had no significant impact on their antiseizure properties in the MES test in mice. Neither CCPA (0.125 mg/kg) administered singly, nor in combinations with conventional AEDs (at their ED50s) affected motor performance in the chimney test and long-term memory in the passive avoidance task. No pharmacokinetic alterations in brain CBZ concentrations were observed after administration of CCPA at 0.125 mg/kg. It may be concluded that CCPA, acting selectively on adenosine A1 receptors, enhances pharmacodynamically the antiseizure effect of CBZ in the MES test.

Omeprazole affects neither electroconvulsive threshold nor anticonvulsant activity of diphenylhydantoin and carbamazepine in mice.

Omeprazole is a commonly prescribed drug for patients with peptic ulcerations. Its main mechanism of action is related to inhibition of H(+)-K(+)-ATP-ase, albeit it may also block carbonic anhydrase. This study evaluates the effects of acute and prolonged (3- or 7-day) intragastrical administration of omeprazole on the anticonvulsant activity of carbamazepine or diphenylhydantoin against maximal electroshock-induced seizures in mice. Omeprazole administered acutely, for 3 days or 7 days did not alter the electroconvulsive threshold in mice. Moreover, the drug did not affect the anticonvulsant activity of the tested antiepileptic drugs.

Effect of histamine receptor antagonists on aminophylline-induced seizures and lethality in mice.

The aim of this study was to evaluate the effects of H(1) (antazoline and astemizole) or H(2) (cimetidine and famotidine) histamine receptor antagonists on the clonic phase, tonic seizures and morality of mice challenged with aminophylline to induce convulsions in mice. Moreover, the total plasma and brain concentrations of theophylline were evaluated. Astemizole (1 mg/kg) did not affect the threshold for aminophylline-induced seizures, but when administered at a dose of 2 mg/kg, it significantly reduced the CD(50) value of aminophylline from 249 mg/kg to 211 mg/kg (p < 0.01). The remaining histamine receptor antagonists studied i.e., antazoline (up to 1 mg/kg), cimetidine (up to 40 mg/kg) and famotidine (up to 10 mg/kg) had no impact on seizure susceptibility in aminophylline-induced convulsions. Furthermore, astemizole (2 mg/kg) decreased latency to the clonic phase of aminophylline-induced convulsions from 51.1 +/- 4.5 to 32.1 +/- 4.3 min (p < 0.01). It is noteworthy that astemizole, a novel H(1) receptor antagonist, did not alter the brain and plasma levels of theophylline, so the existence of pharmacokinetic interactions was excluded. Our results indicate that some interactions between methylxanthines and histamine receptor antagonists may be clinically important since these drugs are usually combined during the treatment of status asthmaticus.

Effects of some convulsant agents on the protective activity of topiramate against maximal electroshock-induced seizures in mice.

The anticonvulsant activity of topiramate combined with some convulsant agents (bicuculline--BIC, N-methyl-D-aspartate--NMDA, and kainic acid--KA), given at subconvulsive doses, was evaluated in the maximal electroshock (MES)-test in mice. BIC (1.5 mg/kg), KA (10 mg/kg) and NMDA (50 mg/kg) significantly decreased the anticonvulsant activity of topiramate raising its ED(50) from 76.2 mg/kg to 135, 102, and 107 mg/kg, respectively. BIC (0.75 mg/kg) and KA (5 mg/kg) did not alter the protective activity of topiramate in the MES-test. Moreover, topiramate injected alone (up to 135 mg/kg) did not affect motor performance and long-term memory of animals tested in the chimney and passive avoidance tests, respectively. In contrast, combinations of topiramate with BIC (1.5 mg/kg), NMDA (50 mg/kg) or KA (10 mg/kg) considerably disturbed long-term memory in mice. Additionally, co-administration of topiramate with KA (10 mg/kg) or BIC (1.5 mg/kg) significantly impaired motor performance, whereas topiramate co-administered with NMDA (50 mg/kg) had no impact on motor coordination in mice. None of the studied convulsants affected the free plasma concentration of topiramate assayed with immunofluorescence method. The results of this study seem to indicate the expression of the anticonvulsant activity of topiramate is dependent on all ionotropic glutamate and GABAA receptor-mediated events.

Effect of lamotrigine combined with felbamate on the horizontal (ambulatory) activity in mice.

Exploratory and spontaneous locomotor activities, after administration of some novel antiepileptic drugs (felbamate and lamotrigine alone or in combination), were evaluated in mice by means of the electronically monitored locomotor activity system (Digiscan analyzer). Felbamate (injected intraperitoneally, at the single dose of 25.7 mg/kg) significantly reduced behavioral activity in terms of horizontal (ambulatory) activity in mice. The combination of felbamate (25.7 mg/kg) with lamotrigine (2.3 mg/kg) drastically reduced this parameter during the first 15-min period (habituation to a novel environment--being the rate of exploratory locomotor activity) and the second 15-min interval (spontaneous locomotor activity). Moreover, neither the exploratory, nor spontaneous locomotor activity of the mice, were affected by lamotrigine (at the separate dose of 2.3 mg/kg) with respect to the ambulatory activity of the animals tested. Felbamate administered alone or combined with lamotrigine considerably impaired exploratory and spontaneous locomotor activities of the animals tested in terms of horizontal activity.

Influence of LY 300164 alone or in combination with carbamazepine or diphenylhydantoin on the body temperature in mice.

This study was aimed at evaluating the body temperature of mice following the injection of LY 300164, an AMPA/kainate receptor antagonist, alone or in combination with carbamazepine or diphenylhydantoin. LY 300164, injected alone at the dose of 2 mg/kg, produced a potent hypothermic effect between 15 and 30 min, or 60 and 90 min, after the drug administration. The combined treatment of LY 300164 (2 mg/kg) with diphenylhydantoin (3.6 mg/kg) resulted in a significant decrease of body temperature at the time period between 0 and 30 min, whilst LY 300164 (2 mg/kg) co-administered with carbamazepine (5 mg/kg) did not affect the animal temperature. Moreover, either diphenylhydantoin (11.8 mg/kg) or carbamazepine (15.8 mg/kg) injected alone exerted the hypothermic effects elicited at times ranging between 0 and 15 min, or 60 and 90 min, after the respective drug dose administration. In conclusion, hypothermia induced by LY 300164 along with its neuroprotective effects, may be useful in various brain conditions related with neuronal loss in which hypothermia offers some profitable effects, prolonging a survival rate of neurons in the central nervous system.