Monika Banach

In this study, we assessed the impact of repeated valproate administration on its anticonvulsant effects and side effects in mice. We measured the plasma and brain concentrations of valproate and examined changes in the expression of selected genes in the mouse hippocampus after both acute and chronic treatments. Electroconvulsions were induced using an alternating current (50 Hz, 25 mA, 0.2 s) through ear clip electrodes. Motor impairment and long-term memory deficits were assessed with the chimney test and passive avoidance task. Valproate concentrations in the brain and plasma were measured by a fluorescence polarization immunoassay. mRNA was isolated using a modified Chomczyński and Sacchi method, and RQ-PCR was performed with an Applied Biosystems 7900 using SDS and RQ Study software. The 50% effective dose (ED₅₀) of valproate in the 14 × 2 protocol was significantly lower than the control. Despite no observed memory deficits in chronic protocols, the 50% toxic dose (TD₅₀) for motor impairment was also significantly lower. Chronic valproate treatment did not alter the plasma and brain concentrations. However, the expression levels of three genes (CACNA1G, GAD1, SCN1A) were significantly higher in the chronic protocols with the higher dose of valproate compared to single protocols, suggesting a dose-dependent effect. The repeated administration of valproate resulted in both enhanced efficacy and increased toxicity in terms of motor impairment. The observed effect may be associated with transcriptional adaptations potentially mediated by epigenetic mechanisms rather than with pharmacokinetic events. To enhance the reliability of the results obtained in animal epilepsy models, antiepileptic drugs should be administered chronically.

The objective of this study is to evaluate the anticonvulsant efficacy of carbamazepine (CBZ) following acute and chronic administration across four treatment protocols in a murine model of maximal electroshock-induced seizures. A single dose of the drug was utilized as a control. The neurotoxic effects were evaluated in the chimney test and the passive avoidance task. Furthermore, plasma and brain concentrations of CBZ were quantified across all treatment protocols. The subchronic administration of CBZ (7 × 2 protocol) resulted in an attenuation of its antielectroshock effect. In the three remaining treatment regimens (7 × 1, 14 × 1, and 14 × 2) the median effective doses of CBZ were comparable to the control. Neither acute nor chronic treatment with CBZ resulted in a discernible impact on motor coordination or long-term memory. The plasma and brain concentrations of CBZ were significantly lower in most chronic protocols when compared to a single-dose application. This may explain the transient attenuation of CBZ effectiveness in the 7 × 2 protocol, but not the return to the previous level. The anticonvulsant and neurotoxic profiles of CBZ did not differ after single and chronic administration. Therefore, experimental chronic studies with CBZ are not prerequisites for concluding and possibly translating results to clinical conditions.

The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.

Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.

Trimetazidine (TMZ), an anti-ischemic drug for improving cellular metabolism, is mostly administered to patients with poorly controlled ischemic heart disease (IHD). Since IHD is considered the most frequent causative factor of cardiac arrhythmias, and these often coexist with seizure disorders, we decided to investigate the effect of TMZ in the electroconvulsive threshold test (ECT) and its influence on the action of four first-generation antiepileptic drugs in the maximal electroshock test (MES) in mice. The TMZ (up to 120 mg/kg) did not affect the ECT, but applied at doses of 20–120 mg/kg it decreased the antielectroshock action of phenobarbital. The TMZ (50–120 mg/kg) reduced the effect of phenytoin, and, when administered at a dose of 120 mg/kg, it diminished the action of carbamazepine. All of these revealed interactions seem to be pharmacodynamic, since the TMZ did not affect the brain levels of antiepileptic drugs. Furthermore, the combination of TMZ with valproate (but not with other antiepileptic drugs) significantly impaired motor coordination, evaluated using the chimney test. Long-term memory, assessed with a passive-avoidance task, was not affected by either the TMZ or its combinations with antiepileptic drugs. The obtained results suggest that TMZ may not be beneficial as an add-on therapy in patients with IHD and epilepsy.

A correction to this paper has been published: https://doi.org/10.1007/s43440-021-00275-7

Accumulating experimental studies show that antiarrhythmic and antiepileptic drugs share some molecular mechanisms of action and can interact with each other. In this study, the influence of amiodarone (a class III antiarrhythmic drug) on the antiseizure action of four second-generation antiepileptic drugs was evaluated in the maximal electroshock model in mice. Amiodarone, although ineffective in the electroconvulsive threshold test, significantly potentiated the antielectroshock activity of oxcarbazepine and pregabalin. Amiodarone, given alone or in combination with oxcarbazepine, lamotrigine, or topiramate, significantly disturbed long-term memory in the passive-avoidance task in mice. Brain concentrations of antiepileptic drugs were not affected by amiodarone. However, the brain concentration of amiodarone was significantly elevated by oxcarbazepine, topiramate, and pregabalin. Additionally, oxcarbazepine and pregabalin elevated the brain concentration of desethylamiodarone, the main metabolite of amiodarone. In conclusion, potentially beneficial action of amiodarone in epilepsy patients seems to be limited by neurotoxic effects of amiodarone. Although results of this study should still be confirmed in chronic protocols of treatment, special precautions are recommended in clinical conditions. Coadministration of amiodarone, even at low therapeutic doses, with antiepileptic drugs should be carefully monitored to exclude undesired effects related to accumulation of the antiarrhythmic drug and its main metabolite, desethylamiodarone.

Introduction: As a matter of course, elderly people are more sensitive to both the pharmacological and toxicological effects of pharmacotherapy. A senior’s treatment, therefore, requires more attention compared to younger adults. Extended release (ER) formulations of anti-epileptic drugs (AEDs) have been developed to improve safety, efficacy and long-term adherence. In senior patients, ER AEDs are used to treat epilepsy, psychiatric conditions, and neuropathic pain. However, very limited clinical evidence is available on the use of these ER AEDs in these populations. Areas covered: The authors of this paper have identified clinical studies of ER AED formulations used in elderly populations through literature searches looking, both, at their use in epileptic and non-epileptic indications. Additionally, immediate release (IR) and ER formulations of AEDs were compared whenever possible. Expert opinion: The broad use of ER AED formulations in elderly patients with swallowing problems is limited by the fact that ER AED tablets (or capsules) must not be cut, crushed or chewed. The only exception is the ER formulation of valproate or topiramate which can be mixed with soft food. Although, the ER formulations of AEDs seem better tolerated than the IR equivalents, a possibility of numerous interactions with drugs prescribed for other reasons must be carefully considered.

Neurosteroids were initially defined as steroid hormones locally synthesized within the nervous tissue. Subsequently, they were described as steroid hormone derivatives that devoid hormonal action but still affect neuronal excitability through modulation of ionotropic receptors. Neurosteroids are further subdivided into natural (produced in the brain) and synthetic. Some authors distinguish between hormonal and regular neurosteroids in the group of natural ones. The latter group, including hormone metabolites like allopregnanolone or tetrahydrodeoxycorticosterone, is devoid of hormonal activity. Both hormones and their derivatives share, however, most of the physiological functions. It is usually very difficult to distinguish the effects of hormones and their metabolites. All these substances may influence seizure phenomena and exhibit neuroprotective effects. Neuroprotection offered by steroid hormones may be realized in both genomic and non-genomic mechanisms and involve regulation of the pro- and anti-apoptotic factors expression, intracellular signaling pathways, neurotransmission, oxidative, and inflammatory processes. Since regular neurosteroids show no affinity for steroid receptors, they may act only in a non-genomic mode. Multiple studies have been conducted so far to show efficacy of neurosteroids in the treatment of the central and peripheral nervous system injury, ischemia, neurodegenerative diseases, or seizures. In this review we focused primarily on neurosteroid mechanisms of action and their role in the process of neurodegeneration. Most of the data refers to results obtained in experimental studies. However, it should be realized that knowledge about neuroactive steroids remains still incomplete and requires confirmation in clinical conditions.