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Background: Anticonvulsant and acute toxic effects of 5-[(3-fluorophenyl)ethyl]-4-(n-hexyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPF-34)—a candidate for novel antiepileptic drug—were examined in the maximal electroshock-induced seizure (MES) model and rotarod test in mice. The interaction profile of TPF-34 with four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was also studied in the mouse MES model. Methods: Both ED50and TD50values for TPF-34 were determined at four treatment times (15, 30, 60 and 120 min after i.p. administration) in the MES model and rotarod test in adult male albino Swiss mice, respectively. The influence of TPF-34 on the protective anticonvulsant action of carbamazepine, phenobarbital, phenytoin and valproate in the mouse MES model was assessed with isobolographic analysis of interaction. Total brain antiepileptic drug concentrations were measured with fluorescence polarization immunoassay. Results: TPF-34, when administered alone at four pretreatment times (15, 30, 60 and 120 min before experiments), possessed a favorable preclinical profile with the protective index (a ratio of TD50and ED50values) ranging from 2.89 to 3.53. Moreover, TPF-34, when combined with carbamazepine, phenobarbital, phenytoin and valproate, exerted an additive interaction in the MES model in mice. TPF-34 had no impact on total brain antiepileptic drug concentrations in mice. Conclusions: A protective index value higher than 3 allows recommending TPF-34 as a promising antiepileptic drug candidate for further preclinical testing using other experimental seizure models. The additive interaction of TPF-34 with carbamazepine, phenobarbital, phenytoin and valproate in the mouse MES model is worthy of recommendation to further clinical studies.

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).

Background: The aim of this study was to determine the effect of ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel (HCN) blocker) on the threshold for maximal electroshock (MEST)-induced tonic seizures in mice. Methods: Electroconvulsions were produced in mice by means of a current (sine-wave, 50 Hz, maximum 500 V, strength from 3–10 mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Results: Ivabradine administered intraperitoneally (ip), 60 min before the MEST test, at doses of 5 and 10 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, ivabradine at doses of 15 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (p < 0.05 and p < 0.001, respectively). Linear regression analysis of ivabradine doses and their corresponding threshold increases allowed determination of the threshold increasing doses by 20 and 50% (TID20and TID50 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 and TID50values for ivabradine were 8.70 and 18.29 mg/kg, respectively. Conclusions: Based on this preclinical study, one can ascertain that ivabradine dose-dependently increased the threshold for MEST-induced seizures, suggesting the antiseizure activity of the compound in this seizure model in mice.

Background: The aim of this study was to determine the effects of N-(morpholinomethyl)-p-isopropoxy-phenylsuccinimide (MMIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) against maximal electroshock (MES)-induced seizures in mice. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered viaauricular electrodes. Total brain concentrations of AEDs were measured to determine the characteristics of interaction between MMIPPS and classical AEDs in the mouse MES model. Results: MMIPPS administered intraperitoneally (ip) at 100 mg/kg significantly elevated the threshold for electroconvulsions in mice (p < 0.01). MMIPPS at doses of 25 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, MMIPPS (50 mg/kg) significantly enhanced the anticonvulsant activity of PB and VPA(p < 0.05), but not that of CBZ or PHT, in the MES test in mice. Pharmacokinetic studies revealed that MMIPPS (50 mg/kg) did not alter total brain concentrations of PB, but significantly elevated total brain concentrations of VPA in mice (p < 0.05). Conclusions: The enhanced anticonvulsant action of PB by MMIPPS in the mouse MES model and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPAconcentration seems to be responsible for the enhanced anticonvulsant action of VPAby MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint.

Background: Progesterone with its anti-seizure effect plays a role in the pathophysiology of catamenial epilepsy which affects 31-60% of epileptic women. In this study, an attempt to treat women suffering from catamenial epilepsy with progesterone, as an adjuvant drug, was made. Methods: The treatment was given to 36 women aged 20–40 years (mean age: 30.75± 6.05) with seizuresinthe entire second half of the menstrual cycle, who were found to have low serum levels of progesterone on days 22, 27, 28 of the cycle in comparison with a control group of healthy women. The patients were administered progesterone in a daily dose of 50 mg on days 16–25 of each cycle. The serum levels of antiepileptic drugs were assayed. The period of progesterone therapy ranged from 3 to 45 months (17.7 on average). Results: Three patients were free of secondary generalized seizures, and one - of simple partial seizures. A decline in the frequency of primary and secondary generalized seizures by 20-96% (55.9% on average) was accomplished in 18 patients (primary general-izedby20-96% - 54.7%on average, and secondarily generalized by 38-85% - 59%on average). Adeclinein the frequencyof complex partial seizures by 38-87% (63.1% on average) was achieved in 15 women. In 1 patient, the frequency of myoclonic seizures decreased by 46%. There was no improvement in 5 women (3 patients with generalized, 1 with complex partial and 1 with simple partial seizures). An exacerbation of seizure frequency occurred in 5 patients. Adverse effects were not found in any of the subjects. The average concentrations of antiepileptic drugs during hormonal therapy were in the therapeutic range. Conclusion: Progesterone combined with antiepileptic therapy was well tolerated and resulted in a significant reduction of seizure frequency in majority of patients with catamenial epilepsy.

Background: The aim of this study was to determine the effects of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione (TP10) on the protective action of 4 classical antiepileptic drugs - carbamazepine, phenobarbital, phenytoin and valproate - against maximal electroshock-induced seizures in mice. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered viaauricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured, together with total brain antiepileptic drug concentrations. Results: TP10 administered intraperitoneally at 10mg/kg significantly elevated the threshold for electroconvulsions in mice. TP10 at doses of 2.5 and 5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP10 (5 mg/kg) significantly enhanced the anticonvulsant activity of valproate, but not that of carbamazepine, phenobarbital or phenytoin in the maximal electro-shock seizure test in mice. Pharmacokinetic experiments revealed that TP10 significantly elevated total brain concentrations of valproate in mice. Conclusions: The enhanced anticonvulsant action of valproate by TP10 in the mouse maximal electroshock-induced seizure model was associated with a pharmacokinetic increase in total brain valproate concentrations in mice. The combinations of TP10 with carbamazepine, phenobarbital and phenytoin were neutral from a preclinical viewpoint.

Background: The aim of the study was to determine the type of interaction between pregabalin (a 3rd-generation antiepileptic drug) and WIN 55,212-2 mesylate (WIN - a highly potent non-selective cannabinoid CB1 and CB2 receptor agonist) administered in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice. Methods: Linear regression analysis was used to evaluate the dose-response relationships between logarithms of drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, doses were calculated that increased the antinociceptive effect by 30% (ED30values) for pregabalin, WIN, and their combination. The type of interaction between pregabalin and WIN was assessed using the isobolographic analysis. Results: Results indicated that both compounds produced a definite antinociceptive effect, and the experimentally-derived ED30values for pregabalin and WIN, when applied alone, were 29.4 mg/kg and 10.5 mg/kg, respectively. With isobolography, the experimentally derived ED30 mixvalue for the fixed ratio combination of 1:1 was 5.7 mg/kg, and differed significantly from the theoretically calculated ED30 addvalue of 19.95 mg/kg (p < 0.01), indicating synergistic interaction between pregabalin and WIN in the hot-plate test in mice. Conclusions: Isobolographic analysis demonstrated that the combination of WIN with pregabalin at a fixed ratio of 1:1 exerted synergistic interaction in the mouse model of acute thermal pain. If the results from this study could be adapted to clinical settings, the combination of WIN with pregabalin might be beneficial for pain relief in humans.

Dentate granule cell neurogenesis persists throughout life in the hippocampus of mammals. Alterations in this process occur in many neurological diseases, including epilepsy. Among the different types of epilepsy, the most frequent is temporal lobe epilepsy (TLE). Therefore, a number of laboratory studies use animal models of TLE to observe the fate of neuronal cells after seizures. Hippocam-pal neurogenesis is very sensitive to physiological and pathological stimuli. Seizures, as pathological stimuli, alter both the extent and the pattern of neurogenesis, which is associated with cognitive function. Various alterations in neurogenesis are observed depending on the amount of time that has elapsed after the seizures. In acute seizures, neurogenesis generally increases, whereas in chronic epilepsy, neurogenesis decreases. Moreover, several methods currently used for the treatment of brain disorders such as TLE can also have significant impacts on cognitive functions. This review is focused on the recent findings regarding neurogenesis in animal models of TLE.

Nefopam is a centrally acting non-opioid analgesic with a mechanism of action that is not completely understood. Adverse effects associated with the therapeutic use and overdose of nefopam are mainly associated with the central nervous system, such as hallucinations, cerebral edema and convulsions. The aim of this study was to assess the effect of nefopam on the electrical threshold and its influence on the protective activity of antiepileptic drugs in the maximal electroshock test in mice. A 5 mg/kg dose of nefopam significantly elevated the electric seizure threshold, while a dose of 1 mg/kg failed to protect mice against electroconvulsion. At a subthreshold dose of 1 mg/kg, nefopam significantly enhanced the anticonvulsant activity of valproate against electroconvulsions. The protective activity of phenobarbital and phenytoin was significantly enhanced by co-administration of nefopam at the 5 mg/kg dose, but this same dose of nefopam failed to affect the protective activity of carbamazepine. In conclusion, nefopam exerts an anticonvulsive effect when given alone and significantly enhances the protective activity of certain antiepileptic agents against electroconvulsions induced in mice.

The objective of this study was to determine the effects of 7-nitroindazole (7NI - a preferential neuronal nitric oxide synthase (NOS) inhibitor) and NG-nitro-L-arginine (NNA - a non-selective NOS inhibitor) on the anticonvulsant action of pregabalin (PGB — a third-generation antiepileptic drug) in the maximal electroshock (MES)-induced seizure model in mice. Electroconvulsions were produced in mice by means of an alternating current (50 Hz, 500 V, 25 mA, ear-clip electrodes, 0.2 s stimulus duration, tonic hindlimb extension taken as the endpoint). The anticonvulsant action of PGB in the MES test was expressed as median effective doses (ED50 values) of the drug, protecting 50% of animals tested against MES-induced seizures. The acute adverse-effect potentials of PGB in combination with 7NI and NNA were evaluated in the chimney test (motor coordination), step-through passive avoidance task (long-term memory) and grip-strength test (skeletal muscular strength) in mice.

This study was designed to determine the effects of p-isopropoxyphenylsuccinimide monohydrate (IPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model.

The aim of this study was to assess the acute adverse effects (neurotoxic) of several antiepileptic drugs (clonazepam, lamotrigine, oxcarbazepine, phenytoin, phenobarbital and topiramate) by measuring skeletal muscular strength in mice using the grip-strength test. Linear regression analysis of grip-strength in relation to drug dose-response allowed us to determine D50 values, the dosages of antiepileptic drugs that reduced grip-strength in mice by 50% compared to control animals. Each of the antiepileptic drugs studied reduced skeletal muscular strength in mice in a dose-dependent manner. The D50 for clonazepam was 31.7 mg/kg, lamotrigine - 47.7 mg/kg, oxcarbazepine - 87.3 mg/kg, phenobarbital - 128.7 mg/kg, phenytoin - 69.7 mg/kg, and topiramate - 509.5 mg/kg. In conclusion, the grip-strength test can aid in evaluating acute adverse effects of drugs with respect to their influence on muscular strength in experimental animals.

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