Maximal Electroshock-induced Seizures Research Articles

Isobolographic additivity among lacosamide, lamotrigine and phenobarbital in a mouse tonic-clonic seizure model.

Epilepsy is a serious neurological disease affecting about 1% of people worldwide (65 million). Seizures are controllable with antiepileptic drugs (AEDs) in about 70% of epilepsy patients, however, there remains about 30% of patients inadequately medicated with these AEDs, who need a satisfactory control of their seizure attacks. For these patients, one of the treatment options is administration of 2 or 3 AEDs in combination. To determine the anticonvulsant effects of a combination of 3 selected AEDs (i.e., lacosamide - LCM, lamotrigine - LTG and phenobarbital - PB) at the fixed-ratio of 1:1:1 in a mouse maximal electroshock-induced (tonic-clonic) seizure model by using isobolographic analysis. Seizure activity was evoked in adult male albino Swiss mice by a current (sinewave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis was used to detect interaction for the 3-drug combination. With type I isobolographic analysis, the combination of LCM, LTG and PB (at the fixed-ratio of 1:1:1) exerted additive interaction in the mouse maximal electroshock-induced (tonic-clonic) seizure model. The combination of LCM with LTG and PB produced additive interaction in the mouse tonicclonic seizure model, despite various molecular mechanisms of action of the tested AEDs.

QSAR modeling of some anticonvulsant molecules as γ-aminobutyrate-aminotransferase inhibitors

Abstract Quantitative structure-activity relationship study was done on 62 compounds with anticonvulsant activity in maximal electroshock-induced seizures test. The molecular structure of the compounds was optimized with parametric semi-empirical PM3 method available in Spartan 14 software. Quantum mechanical descriptors were extracted from the property and output module of the software. Combination of activity based-clustering and genetic function algorithm chemo-metric techniques were used to map molecular descriptors to activity values. A well-validated and robust quantitative structure-activity model was obtained with R 2 = 0.947, Q 2 = 0.924, F = 91.42 and R 2 pred(test) = 0.881. The descriptor contained in the model suggested an increase in the number of O and N atoms in the molecule augments the activity of the studied compounds. Also, the introduction of electron donating substituents is beneficial to the activity of the studied compounds. Armed with these, information, new hypothetical1H-pyrazole-5-carboxylic acid derivatives were designed using template approach and screened in silico . Compounds with hypothetic anticonvulsant activity better than the template were docked with γ-aminobutyrate-aminotransferase and their binding affinity was found to be comparable and even superior to that of 4-aminohex-5-enoic acid (vigabatrin), a known inhibitor of γ-aminobutyrate-aminotransferase.

The anticonvulsant and anti-plasmid conjugation potential of Thymus vulgaris chemistry: An in vivo murine and in vitro study

The high-performance counter-current chromatography was used for the efficient purification of single constituents from Thymus vulgaris essential oil. Mixtures of n-heptane, ethyl acetate, methanol, and water (5:2:5:2 and 4:1:4:1 v/v), allowed purification of eugenol, 1-octen-3- ol, borneol, thymol, terpinen-4-ol, and camphor, while n-hexane, acetonitrile, and tert-butyl methyl ether (1:1:0.1 v/v) yielded carvacrol, borneol, linalyl acetate, caryophyllene oxide, p-cymene, and eucalyptol. The anticonvulsant activities were evaluated in the maximal electroshock-induced seizure test in mice model (systemic i. p. administration). The oil exerted protection against MES-induced seizures when administered 15 and 30 min before the tests (50 and 62.5%, respectively). Among the isolates, borneol, thymol, and eugenol exerted the strongest protection against seizures. Moreover, linalool had the ability to reduce the transfer of the pKM101 plasmid by 84%, what has the potential to reduce virulence and resistance spread in E. coli. No acute toxic effects towards the CNS were noticed either for the essential oil or for single compounds, in the chimney and grip-strength tests. The preclinical screening of Thymus vulgaris EO, as well as isolated terpenoids, provides evidence that the EO has partial protective activity against seizures and HPCCC technique is suitable for its large scale isolation.

QSAR STUDIES ON DERIVATIVES OF QUINAZOLINE-4(3H)-ONES WITH ANTICONVULSANT ACTIVITIES

Quantitative structure-activity relationship study was done on some quinazoline-4(3H)-ones derivatives with anticonvulsant activity against maximal electroshock-induced seizure. The quinazoline derivatives used as dataset and their anticonvulsant activity value were obtained from the literature. The molecular structure of the dataset compounds was generated with Spartan 14 software. This was optimized with PM3 semi-empirical quantum mechanical method available in the software. Molecular descriptors were obtained from the optimized structures using the PaDEL-Descriptor software. Activity values of the compounds and molecular descriptors obtained from the optimized structure made up the database for the study. The database was divided into training and test sets with Kennard Stone algorithm. Genetic function algorithm was used to develop quantitative structure-activity relationship models. The best model obtained was stable, robust and had good statistical parameters including determination coefficient R2 (0.899), adjusted determination coefficient R2adj (0.888), variance ratio F (82.03), leave one out cross-validated determination coefficient Q2 (0.866) and predicted determination coefficient for the test set R2pred (0.7406). The model indicated that the anticonvulsant activity of the studied compounds was dependent on Broto-Moreau autocorrelation-lag2/weighted by Vander Waals volume (ATS2v), average coefficient sum of the last eigenvector from Barysz matrix/weighted by Vander Waals volume (VE2_DZv), largest absolute eigenvalue of Burden matrix-6/weighted by relative atomic mass (SpMax6_Bhm), average valence path of order 6 and radial distribution function at 4.5 interatomic distance weighted by first ionization potential (RDF45i).

The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.

De novo mutations of SCN8A, encoding the voltage-gated sodium channel NaV 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4-5months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential for toxicity. Functional characterization of several SCN8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases. The novel sodium channel modulator GS967 has greater preference for persistent as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8aN1768D/+ mouse model carrying an SCN8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8aN1768D/+ mice. GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8aN1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against maximal electroshock-induced seizures in Scn8aN1768D/+ and wild-type mice. Chronic treatment of Scn8aN1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8aN1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.

Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands

As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2−25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0–120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.

Synthesis, evaluation, and molecular properties prediction of substituted cinnamoylpiperazine derivatives as potential antinociceptive and anticonvulsive agents

A series of novel cinnamoylpiperazine derivatives (5a–5l) were synthesized as potential antinociceptive, and anticonvulsive agents. Various heterocyclic systems like piperidine, morpholine, piperazine, and N-arylpiperazine were combined with cinnamoyl or methylenedioxy cinnamoyl moieties to obtain a series of constrained analogs of cinnamides. Of these, compound 5e possessing 4-fluorophenyl substitution on the piperazine ring exhibited good antinociceptive activity in capsaicin and formalin-induced nociception methods, and also significant anticonvulsant activity in pentylenetetrazole and maximal electroshock-induced seizure methods. Further, all the derivatives were studied for molecular and preadmet properties. The activities of compound 5e were supported by molecular and preadmet properties for its in silico oral bioavailability and drug-likeness.

Amiodarone, a multi-channel blocker, enhances anticonvulsive effect of carbamazepine in the mouse maximal electroshock model

Cardiac arrhythmia may occur in the course of epilepsy. Simultaneous therapy of the two diseases might be complicated by drug interactions since antiarrhythmic and antiepileptic agents share some molecular targets. The aim of this study was to evaluate the influence of amiodarone, an antiarrhythmic drug working as a multi-channel blocker, on the protective activity of four classical antiepileptic drugs in the maximal electroshock test in mice. Amiodarone at doses up to 75 mg/kg did not affect the electroconvulsive threshold in mice. Acute amiodarone at the dose of 75 mg/kg significantly potentiated the anticonvulsive effect of carbamazepine, but not that of valproate, phenytoin or phenobarbital in the maximal electroshock-induced seizures in mice. The antiarrhythmic agent and its combinations with antiepileptic drugs did not impair motor performance or long-term memory in mice, except for the combination of amiodarone and phenobarbital. Brain concentrations of antiepileptic drugs were not changed. Despite favourable impact of amiodarone on the anticonvulsive action of carbamazepine in the maximal electroshock, co-administration of the two drugs should be carefully monitored in clinical conditions. Further studies are necessary to evaluate effects of chronic treatment with amiodarone on seizure activity and the action of antiepileptic drugs.

Additive interaction for three-drug combination of carbamazepine, lacosamide and lamotrigine against maximal electroshock-induced seizures – a type I isobolographic analysis

Additive interaction for three-drug combination of carbamazepine, lacosamide and lamotrigine against maximal electroshock-induced seizures – a type I isobolographic analysis

Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs

ObjectiveThe appropriate use of analgesic drugs based on their degree of analgesia and adverse effects is important for pain management. Although it has been reported that AM404, a metabolite of acetaminophen, has anticonvulsant effects in several animal seizure models, little is known about the relation between acetaminophen and seizures. We therefore investigated the effects of acetaminophen on seizure susceptibility in several mouse seizure and epilepsy models and compared the effects with those of nonsteroidal anti-inflammatory drugs (NSAIDs). MethodsAnticonvulsant activity was evaluated in ICR mice using maximum electroshock-induced seizure tests and acute pentylenetetrazol-induced seizure tests. Electrical kindling via corneal stimulation and pentylenetetrazol administration were used to establish animal kindling epilepsy models. Proconvulsive activity was examined using an electroconvulsive shock test with low-stimulus currents. ResultsAcetaminophen showed slight, but not statistically significant, anticonvulsant activity in both the maximum electroshock-induced seizure test (300–600mg/kg i.p.) and acute pentylenetetrazol-induced seizure test (100–600mg/kg i.p.). In contrast, acetaminophen exhibited significant anticonvulsant effects in corneal electroshock-kindled and pentylenetetrazol-kindled mice (ED50 values: 251 and 310mg/kg i.p., respectively). When the proconvulsive effects of NSAIDs were examined in the low-current electroconvulsive shock-induced seizure model, the nonselective cyclooxygenase (COX)-1 and COX-2 inhibitors indomethacin, diclofenac, and loxoprofen induced dose-dependent proconvulsant activity. Celecoxib, a COX-2 selective inhibitor, had no proconvulsant activity. ConclusionThese findings suggest that acetaminophen has a significant anticonvulsant effect and that its profile is completely different from that of NSAIDs.

Interactions of aliskiren, a direct renin inhibitor, with antiepileptic drugs in the test of maximal electroshock in mice

Experimental studies showed that certain angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor antagonists can decrease seizure severity in rodents. Additionally, some of these blockers of the renin-angiotensin system have been documented to enhance the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures. The aim of the current study was to investigate the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, on the protective action of numerous antiepileptic drugs (carbamazepine, valproate, clonazepam, phenobarbital, oxcarbazepine, lamotrigine, topiramate and pregabalin) in the test of maximal electroshock in mice. The examined drugs were administered intraperitoneally. Aliskiren up to a dose of 75mg/kg did not affect the threshold for electroconvulsions, however, aliskiren (75mg/kg) enhanced the anticonvulsant action of clonazepam and valproate. Following aliskiren treatment, a higher brain concentration of valproate was noted, suggesting a pharmacokinetic interaction. In the rota-rod test, the concomitant treatment with aliskiren (50 or 75mg/kg) and clonazepam (22.6mg/kg) impaired motor coordination while clonazepam (22.6mg/kg) alone showed strong tendency towards this impairment. The combination of aliskiren (75mg/kg) with phenobarbital (25.5mg/kg) caused long-term memory deficits in the passive avoidance task. This study shows that there are no negative interactions between aliskiren and the examined antiepileptic drugs as concerns their anticonvulsant activity. Aliskiren even potentiated the anticonvulsant action of clonazepam and valproate against maximal electroshock. The impact of aliskiren alone on seizure activity or on the anticonvulsant and adverse activity of antiepileptic drugs needs further evaluation in other animal models of seizures.

Anticonvulsant effect of the hydroethanolic leaf extract of Psydrax subcordata (DC.) Bridson in murine models

Ethnopharmacological relevancePsydrax subcordata (DC.) Bridson is a tropical medicinal plant used traditionally for the management of epilepsy. However, there is little scientific evidence to support its use. Aim of studyThe current study investigated the anticonvulsant properties of the hydroethanolic leaf extract of Psydrax subcordata (PSE) in animal models. Materials and methodsThe anticonvulsant effects were evaluated in mouse models of acute seizures (pentylenetetrazole-, picrotoxin-, 4-aminopyridine-, strychnine- and maximal electroshock-induced seizure tests) and status epilepticus (Lithium/pilocarpine-induced SE). The role of GABAergic mechanisms in the actions of the extract was also examined by pre-treatment of animals with flumazenil in the pentylenetetrazole test. ResultsThe extract (30, 100 and 300mg/kg, p.o.) significantly delayed the onset and decreased the duration and frequency of pentylenetetrazole- and picrotoxin-convulsions. PSE also reduced the duration of tonic hind limb extensions in the maximal electroshock-induced seizure test. Furthermore, PSE pre-treatment significantly delayed the onset of seizures and improved survival in the 4-aminopyridine-induced seizure test. In the strychnine-induced seizure test, PSE treatment did not significantly affect the latency to convulsions and time until death when compared to controls. PSE exhibited anticonvulsant effects in the lithium/pilocarpine test by delaying the onset of seizures and status epilepticus as well as reducing the severity of seizures and mortality of mice. Again, the anticonvulsant effect of PSE (100mg/kg, p.o.) was blocked by pre-treatment with flumazenil in the PTZ test. ConclusionPSE has anticonvulsant activity in animal models, and this effect may be mediated, at least partly, through GABAergic mechanisms.

Influence of propafenone on the anticonvulsant activity of various novel antiepileptic drugs in the mouse maximal electroshock model.

The main mechanism of action of propafenone (antiarrhythmic drug) involves the inhibition of the fast inward sodium current during phase 0 of the action potential. Sodium channel-blocking activity is also characteristic for some antiepileptic drugs. Therefore, it could be assumed that propafenone may also affect seizures. In the present study, we evaluated the effect of propafenone on the protective effect of oxcarbazepine, lamotrigine, topiramate and pregabalin against the maximal electroshock-induced seizures in mice. Anticonvulsant activity of propafenone was assessed with the maximal electroshock seizure threshold (MEST) test. Influence of propafenone on the anticonvulsant activity of antiepileptic drugs was estimated in the mouse maximal electroshock model (MES). Drug-related adverse effects were determined in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Brain concentrations of antiepileptics were assessed by fluorescence polarization immunoassay. Propafenone at doses 60-90mg/kg significantly increased the threshold of seizures, in turn at doses 5-50mg/kg did not affect this parameter. Administration of propafenone at the subthreshold dose of 50mg/kg increased antielectroshock activity of oxcarbazepine, topiramate and pregabalin, but not that of lamotrigine. As regards adverse effects, propafenone alone and in combination with antiepileptic drugs did not significantly impair motor coordination or long-term memory in mice. Propafenone (50mg/kg) significantly increased the brain level of pregabalin. Brain concentrations of topiramate and oxcarbazepine were not affected. Our findings show that propafenone has own anticonvulsant action and enhances efficacy of oxcarbazepine, topiramate and pregabalin, but not that of lamotrigine, at least in experimental condition.

Novel Mannich-bases as Potential Anticonvulsants: Syntheses, Characterization and Biological Evaluation.

Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5-benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity. Synthesis, characterization, structure activity relationship and anticonvulsant activity of the Mannich bases of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. All the derivatives were synthesized in three steps. In the first step, substituted 4-hydroxy chalconylbenzene was synthesized by the reaction of 4-hydroxyacetophenone and substituted benzaldehyde, in the presence of potassium hydroxide. In the second step, 2,3-dihydro- 1,5- benzothiazepines and 2,3-dihydro-1,5-benzoxazepines were synthesized by the reaction of 2- thio/aminophenol with chalcones in the presence of glacial acetic acid. In the third step, these compounds finally underwent Mannich reaction with different secondary amines to the respective title compounds. All the synthesized derivatives were characterised and evaluated for anticonvulsant activity using MES (Maximal Electroshock Induced Seizure) and INH (Isoniazide Induced Convulsion) models. The synthesized derivatives were found to be more active in the MES model than INH model, with phenytoin and diazepam being the standards respectively. Accordingly, the mode of action of the synthesized compounds may be similar to phenytoin. The methyl piperazine containing compound, at a dose of 30 mg/kg., was found to be the most active and promising compound in the series. The benzothiazepine derivatives showed better anticonvulsant activity than the benzoxazepines derivatives.

Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis

Background/Aim: To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice. Methods: Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1:1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by high-pressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs. Results: Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1:1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction. Conclusion: LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy.

Time-of-day influences on respiratory sequelae following maximal electroshock-induced seizures in mice.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Although specific mechanisms underlying SUDEP are not well understood, evidence suggests most SUDEP occurs due to seizure-induced respiratory arrest. SUDEP also tends to happen at night. Although this may be due to circumstances in which humans find themselves at night, such as being alone without supervision or sleeping prone, or to independent influences of sleep state, there are a number of reasons why the night (i.e., circadian influences) could be an independent risk factor for SUDEP. We explored this possibility. Adult male WT mice were instrumented for EEG, EMG, and EKG recording and subjected to maximal electroshock (MES) seizures during wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep during the nighttime/dark phase. These data were compared with data collected following seizures induced during the daytime/light phase. Seizures induced during the nighttime were similar in severity and duration to those induced during the daytime; however, seizures induced during the nighttime were associated with a lesser degree of respiratory dysregulation and postictal EEG suppression. Seizures induced during REM sleep during the nighttime were universally fatal, as is seen when seizures are induced during REM during the daytime. Taken together, these data implicate a role for time of day in influencing the physiological consequences of seizures that may contribute to seizure-induced death.NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP frequently occurs during the night, which has been attributed to an effect of sleep. We have shown that sleep state does indeed influence survival following a seizure. That SUDEP occurs during the night could also implicate a circadian influence. In this study we found that time of day independently affects the physiological consequences of seizures.

A novel QSAR model for designing, evaluating,and predicting the anti-MES activity of new 1H-pyrazole-5-carboxylic acid derivatives

A quantitative structure–activity relationship (QSAR) study was performed to develop a model that relates the structures of 62 compounds, which have activity against maximal electroshock induced seizure (MES), with their anti-MES activity. Molecular structures of the compounds were geometrically optimized and energetically minimized using a combination of modified Merck force field (MMFF) molecular mechanics, Austin model 1 (AM1) semi-empirical quantum mechanical and density functional theory (DFT) quantum mechanical method using the Becke’s three parameter exchange functional (B3) hybrid with Lee, Yang and Parr correlation functional (LYP) and basis set of the double zeta split valence plus polarization quality 6-31G** i.e. B3LYP/6-31G**. Theoretically derived descriptors were obtained from the optimized structures, a genetic function approximation (GFA) algorithm was also applied to select the optimal descriptors and multiple linear regression (MLR) was used to establish a relationship between the anti-MES activity of the compounds and the optimal molecular descriptors. A six-parametric equation containing dipole moment (μ), energy of the lowest unoccupied molecular orbital ( ϵ LUMO), polar surface area (PSA), accessible surface area derived from wave function (WAA), sum of the square root of square of the charge on all atom of the molecule (QA) and sum of the square root of square of the charge on all fluorine atom in the molecule was obtained as the QSAR model in the present study with good statistical qualities (R 2 =0.937, R 2 adj =0.928, F=104.11, R 2 pred =0.929 and Q 2 =0.913). The QSAR model was used to study estimate the anti-MES activities of 1H-pyrazole-5-carboxylic acid derivatives not yet synthesized. 10 out of the 101 screened compounds had improved anti-MES activity when compared to the template (i.e. ethyl 4-(4-chlorophenyl)-3-morpholino-1H-pyrrole-2-carboxylate, which is compound number 61 in the dataset) used to design the 101 derivatives. These 10 compounds were docked with voltage-gated sodium channel (PDB code: 2KaV) and there binding affinity were found to were found to be comparable to that of phenytoin (a standard drug known to possess anti-MES activity).

Ivabradine attenuates the anticonvulsant potency of lamotrigine, but not that of lacosamide, pregabalin and topiramate in the tonic-clonic seizure model in mice

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved not only in synaptic transmission and neuronal excitability under physiological conditions, but also in seizure activity. To determine the influence of ivabradine (an HCN channel inhibitor) on the anticonvulsant potency of four novel antiepileptic drugs (AEDs: lacosamide, lamotrigine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure (MES) model. Adult male albino Swiss mice were challenged with maximal electroconvulsions (electric current of 25mA delivered via auricular electrodes). Total brain concentrations of AEDs were measured with high-pressure liquid chromatography. Ivabradine (10mg/kg, i.p.) significantly reduced the anticonvulsant potency of lamotrigine by elevating the ED50 value of the AED from 7.48 (6.15–9.11) to 10.07 (8.85–11.45) mg/kg (P<0.05) in the mouse MES model. In contrast, ivabradine (10mg/kg, i.p.) did not significantly affect the anticonvulsant potency of lacosamide, pregabalin or topiramate in the mouse MES model. Additionally, ivabradine had no impact on total brain concentrations of all the studied AEDs in mice. A special caution is advised when combining ivabradine with lamotrigine in epilepsy patients due to the possible pharmacodynamic reduction of the anticonvulsant action of the later drug. The combinations of ivabradine with lacosamide, pregabalin and topiramate seem to be pharmacodynamic and neutral from a preclinical viewpoint.

Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.

Anti-epileptic Effects of Valepotriate Isolated from Valeriana jatamansi Jones and Its Possible Mechanisms.

Objective:This work aimed to investigate the anti-epileptic effects of valepotriate isolated from Valeriana jatamansi Jones and studied its possible mechanisms.Methods:The anti-epileptic effects of valepotriate were studied using maximal electroshock-induced seizure (MES), pentylenetetrazole (PTZ)-induced epilepsy, and pentobarbital sodium-induced sleeping model in mice. The possible anti-epileptic mechanisms of valepotriate were investigated by analyzing the expressions of GABAA, GABAB, glutamic acid decarboxylase (GAD65), Bcl-2, and caspase-3 in the brain using Western blot assay.Results:The results indicated that valepotriate showed significant anti-epileptic activity against MES- and PTZ-induced epilepsy at doses of 5, 10, and 20 mg/kg, and ED50 values for MES- and PTZ-induced epilepsy were 7.84 and 7.19 mg/kg, respectively. Furthermore, valepotriate (10 and 20 mg/kg) can significantly prolong sleeping time and shorten the latency time on the pentobarbital sodium-induced sleeping time test. Furthermore, valepotriate (5, 10, and 20 mg/kg) could significantly up-regulate the expression of GABAA, GAD65, and Bcl-2 and down-regulate the expression of caspase-3, but had no significant effect on the expression of GABAB.Conclusion:The results indicated that valepotriate had anti-epileptic activity and the mechanisms might be associated with regulation of GABA and inhibition of neuronal apoptosis.SUMMARY Anti-epileptic effect of valepotriate was investigated for the 1st timeValepotriate showed notable anti-epileptic activityValepotriate can significantly increase the expression of GABAA, glutamic acid decarboxylase 65, and Bcl-2 and reduce the expression of caspase-3.