MES-induced Seizures In Mice Research Articles

Anticonvulsant effects of ivermectin on pentylenetetrazole- and maximal electroshock-induced seizures in mice: the role of GABAergic system and KATP channels

IntroductionIvermectin (IVM) is an antiparasitic medicine that exerts its function through glutamate-gated chloride channels and GABAA receptors predominantly. There is paucity of information on anti-seizure activity of IVM. Moreover, the probable pharmacological mechanisms underlying this phenomenon have not been identified. Materials and methodsIn this study, pentylenetetrazole (PTZ)-induced clonic seizures and maximal electroshock (MES)-induced tonic-clonic seizure models, respectively in mice was utilized to inquire whether IVM could alter clonic seizure threshold (CST) and seizure susceptibility. To assess the underlying mechanism behind the anti-seizure activity of IVM, we used positive and negative allosteric modulators of GABAA (diazepam and flumazenil, respectively) as well as KATP channel opener and closer (cromakalim and glibenclamide, respectively). Data are provided as mean ± S.E.M. After the performance of the variance homogeneity test, a one-way and two-way analysis of variance was used. Fisher's exact test was performed in case of MES. P-value less than 0.05 considered statistically significant. Resultsand Discussion: Our data showed that IVM (0.5, 1, 5, and 10 mg/kg, i.p.) increased CST. Furthermore, flumazenil 0.25 mg/kg, i.p. and glibenclamide 1 mg/kg, i.p., could inhibit the anticonvulsant effects of IVM. Supplementary, an ineffective dose of diazepam 0.02 mg/kg, i.p. or cromakalim 10 μg/kg, i.p. were able to enhance the anticonvulsant effects of IVM. Besides, we figure out that the IVM (1 and 5 mg/kg, i.p.) could delay the onset of first clonic seizure and also might decrease the frequency of clonic seizures induced by PTZ (85 mg/kg, i.p.). Finally, IVM could prevent the incidence and death in MES-induced tonic-clonic seizures. ConclusionBased on the obtained results, it can be concluded that IVM may exert anticonvulsant effects against PTZ- and MES-induced seizures in mice that might be mediated by GABAA receptors and KATP channels.

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic\u2013clonic seizure model in mice

BackgroundCombination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug–drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs.AimTo isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice.Materials and methodThe MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique.ResultsThe three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice.ConclusionsThe synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

Molecular docking, ADMET study and in vivo pharmacological research of N-(3,4-dimetoxyphenyl)-2-{[2-methyl-6-(pyridine-2-yl)-pyrimidin-4-yl]thio}acetamide as a promising anticonvulsant

Introduction: The search for new anticonvulsants for epilepsy treatment with higher efficacy and better tolerability remains important. The aim of the present research was an in silico and in vivo pharmacological study of N-(3,4-di­methoxyphenyl)-2-((2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide (Epirimil) as a promising anticonvulsant.&#x0D; Materials and methods: A 1H and 13C NMR spectroscopy, LS/MS, and an elemental analysis were used to deter­mine Epirimil structure. An ADMET analysis, as well as a docking study using anticonvulsant biotargets, e.g.: GAB­AAR, GABAAT, CA II, NMDAR, and AMPAR, was carried out. Anticonvulsant activity was proved, using PTZ- and MES-induced seizures in rats and mice, and neurotoxicity was determined using a rotarod test. Influence of Epirimil on the psycho-emotional state of the laboratory animals was determined by an open field test.&#x0D; Results and discussion: A synthesis method of a promising anticonvulsant Epirimil was modified. The calculated ADMET parameters and a molecular docking into the active sites of anticonvulsant biotargets allowed evaluating the research prospects and predicting possible mechanisms for implementing anticonvulsant activity. A prominent anticonvulsant activity of Epirimil was established using in vivo studies on the model of PTZ-induced seizures in rats and MES-induced seizures in mice. In terms of toxicity, Epirimil belongs to class IV – low toxic substances. The open field test showed that Epirimil had almost no effect on the animals’ behavioral responses: it neither changed their psy­cho-emotional activity, nor increased their anxiety level. ED50, TD50 and protective index of Epirimil according to its anticonvulsant activity were calculated.&#x0D; Conclusion: The obtained experimental results substantiate the prospects of N-(3,4-Dimethoxyphenyl)-2-((2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)thio)acetamide as a promising active pharmaceutical ingredient having a multifactor mechanism of anticonvulsant activity.&#x0D; Graphical abstract:

Influence of salbutamol on the anticonvulsant potency of the antiepileptic drugs in the maximal electroshock-induced seizures in mice.

β2-Adrenergic receptor agonists are widely used agents in the treatment of asthma or preterm labor. Since prevalence of asthma was shown to be higher in patients with epilepsy and modulation of noradrenergic system activity may modify epilepsy course, the aim of the present study was to examine the effect of salbutamol (SALB), one of the most commonly used β2-adrenergic receptor agonist on the anticonvulsant potency of four classical antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB) in mice subjected to the maximal electroshock (MES)-induced seizures. Seizures were caused by a current delivered through ear-clip electrodes. The influence of AEDs and SALB on animals' motor coordination and memory processes was also evaluated. Single SALB injection did not change, whereas 7 days SALB administration decreased seizure threshold in the MES-induced seizures in mice. Moreover, SALB injected ip for 1 day and for 7 days lowered the antiepileptic activity of PB in the MES-induced seizures in mice, but did not change the effect of other analyzed AEDs: VPA, CBZ or DPH. Butoxamine, a selective β2-adrenergic receptor antagonist, reversed SALB influence on the activity of PB. SALB given alone or in combination with the tested AEDs did not affect animals' motor performance and memory after both single and 7 days administration. Presented results show that SALB may decrease the antiepileptic efficacy of PB. A special caution is advised to patients with epilepsy receiving β2-adrenergic receptors agonists in the pharmacotherapy of pulmonary and obstetrical disorders.

Synthesis and Analysis of Anticonvulsant Activities of New 4-[2-(4- alkoxybenzylamino)ethyl]-2H-1,2,4-triazol-3(4H)-one Derivatives

The present study involved the design and synthesis of new substituted 4-[2-(4- alkoxybenzylamino) ethyl]-2H-1,2,4-triazol-3(4H)-one derivatives (8a-w) starting from 1,2- ethanediamine. The final compounds were screened for their in vivo anticonvulsant activities and neurotoxicities by maximal electroshock (MES) and rotarod tests, respectively. Among the compounds studied, 4-[2-(4-butoxybenzylamino)ethyl]-2H-1,2,4-triazol-3(4H)-one hydrochloride (8b) was found by intraperitoneal administration in mice to be the most potent compound with a median effective dose (ED50) value of 33.2 mg/kg and a high protective index (PI) value of 11.4. Compound 8b showed significant oral activity against MES-induced seizures in mice with an ED50 value of 83.1 mg/kg and a PI of 18.1. The results demonstrated that compound 8b possessed better anticonvulsant activity and higher safety than the marketed drug carbamazepine. Keywords: Anticonvulsant activity, carbamazepine, maximal electroshock test, rotarod test, synthesis, triazolone.

Synthesis and anticonvulsant activity of novel purine derivatives

A series of new purines containing triazole and other heterocycle substituents was synthesized and evaluated for their preliminary anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and rotarod neurotoxicity (TOX) tests. Among the compounds studied, 9-decyl-6-(1H-1,2,4-triazol-1-yl)-9H-purine (5e) was the most potent compound, with a median effective dose of 23.4 mg/kg and a high protective index of more than 25.6 after intraperitoneal administration in mice. Compound 5e showed significant oral activity against MES-induced seizures in mice, with an ED50 of 39.4 mg/kg and a PI above 31.6. These results demonstrate that compound 5e possesses better anticonvulsant activity and is safer than the commercially available drugs carbamazepine and valproate in MES, scPTZ and TOX models.

Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice

BackgroundCytisine (CYT), the most commonly used drug for smoking cessation in Poland, was experimentally found to induce convulsions. There is a lack of studies on the influence of CYT on the anticonvulsant activity of antiepileptic drugs (AEDs). MethodsThe effects of CYT on the anticonvulsant activity of six AEDs were examined in maximal electroshock (MES)-induced seizures in mice. ResultsSingle intraperitoneal (ip) administration of CYTin a subthreshold dose of 2mg/kg antagonized the protective activity of ip phenytoin and lamotrigine against MES-induced seizures in mice. Adose of 1mg/kg did not reverse the protective activity of phenytoin and lamotrigine. CYT in a dose of 2mg/kg had no effect on the anticonvulsive activity of carbamazepine, oxcarbazepine, phenobarbital, and valproate magnesium. ConclusionCYT ability to antagonize the anticonvulsive activity of phenytoin and lamotrigine can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to these drugs resulting in possible breakthrough seizure attacks.

7-Nitroindazole, but not NG-nitro-L-arginine, enhances the anticonvulsant activity of pregabalin in the mouse maximal electroshock-induced seizure model

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, 0.2s 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), stepthrough passive avoidance task (long-term memory) and grip-strength test (skeletal muscular strength) in mice.7NI (50mg/kg, ip) significantly enhanced the anticonvulsant action of PGB by reducing the ED50 value of PGB from 145.0mg/kg to 74.4mg/kg (p<0.01). Similarly, 7NI at the lower dose of 25mg/kg also potentiated the anticonvulsant action of PGB by lowering the ED50 value of PGB from 145.0mg/kg to 117.9mg/kg, although the results did not attain statistical significance. In contrast, NNA (40mg/kg, ip) had no impact on the anticonvulsant effects of PGB. Moreover, none of the examined combinations of PGB with 7NI and NNA affected motor coordination, long-term memory and skeletal muscular strength in mice.Based on this preclinical study, one can conclude that 7NI significantly enhanced and NNA had no effect on the anticonvulsant activity of PGB against MES-induced seizures in mice.

Effect of Gentiana olivieri on experimental epilepsy models

Background:Flowering herbs of Gentiana olivieri Griseb. (Gentianaceae) are widely used as bitter tonic, stomachic, stimulant of appetite, antipyretic, anticonvulsant, antidiabetic and for mental problems in the different regions of Turkey.Objective:To establish the anticonvulsant activity potential of G. olivieri.Materials and Methods:In this work, the ethanol extract of G. olivieri was tested in three doses (200, 750 and 1000 mg/kg) for anticonvulsant activity against seizures produced in mice by pentylenetetrazole (PTZ), picrotoxin (PIC) and maximal electroshock (MES). Neurotoxicity of the ethanol extract was also determined by the Rota rod test to evaluate the safety. Ethosuximide (150 mg/kg), diazepam (0.5 mg/kg) and carbamazepine (30 mg/kg) were used as reference drugs.Results:Intraperitonally, injection of the extract significantly prolonged the onset of seizures at doses of 200 and 750 mg/kg, but did not alter the incidence of PTZ-induced seizures. Onset of PIC-induced seizures was delayed by the injection of the extract (1000 mg/kg). Moreover, only 750 mg/kg of the extract protected 25% of the mice against PIC-induced seizures. On the other hand, G. olivieri extract (200, 750 and 1000 mg/kg) showed a significant protective effect against MES-induced seizures. In the Rota rod test, the ethanol extract (200 mg/kg, ip) induced disturbance in motor coordination.Conclusion:The results indicate that G. olivieri has possessed anticonvulsant activity against MES-induced seizures in mice.

Effect of acute and chronic treatment with milnacipran potentiates the anticonvulsant activity of conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice

Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs. The aim of this study was to investigate the influence of acute and chronic treatment with intraperitoneal milnacipran (MLN), a selective serotonin/noradrenaline reuptake inhibitor, on the protective activity of valproate, carbamazepine (CBZ), phenytoin, or phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by an alternating current (50 Hz, 25 mA) delivered via ear-clip electrodes. Motor coordination and long-term memory were evaluated in the chimney test and passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs (AEDs) were assessed by immunofluorescence. Given acutely, MLN at 10 mg/kg increased the convulsive threshold. Acute MLN applied at the subprotective dose of 5 mg/kg enhanced the anticonvulsant effects of CBZ and PB. Chronic treatment with MLN (5-30 mg/kg once daily for 2 weeks) did not affect either the electroconvulsive threshold or the anticonvulsant action of all studied conventional antiepileptic drugs. Since the antidepressant did not affect brain concentrations of antiepileptics used in the study, the revealed interactions seem to be of pharmacodynamic nature. Moreover, acute and chronic MLN, AEDs, and their combinations did not produce significant motor and long-term memory impairment. Acute, but not chronic, treatment with MLN can increase the effectiveness of some AEDs against MES-induced seizures in mice. It seems that MLN may also be considered as a candidate drug for clinical trials in patients with epilepsy and depressive disorders.

Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Isopentenyloxycoumarin and (2 E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent manner.

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)-induced seizures in mice. Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone-AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue. Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect. Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.

Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED(50) values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.

Agmatine enhances the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock seizure model

Accumulating evidence indicates that agmatine (AGM--an endogenous neuromodulator/neurotransmitter in the brain) exerts the anticonvulsant action in various in vivo experiments. Therefore, the aim of this study was to assess the influence of AGM on the protective action of numerous conventional and newer antiepileptic drugs [carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA)] in the mouse maximal electroshock seizure (MES) model. Results indicate that AGM (up to 100 mg/kg, i.p., 45 min before the test) neither altered the threshold for electroconvulsions nor protected the animals against MES-induced seizures in mice. Moreover, AGM (100 mg/kg, i.p.) significantly enhanced the anticonvulsant effects of PB and VPA in the MES test by reducing their ED50 values from 22.54 to 16.82 mg/kg (P < 0.01) for PB, and from 256.1 to 210.6 mg/kg (P < 0.05) for VPA, respectively. In contrast, AGM at 100 mg/kg (i.p.) had no significant effect on the antielectroshock action of the remaining drugs tested (CBZ, LTG, OXC, PHT, and TPM) in mice. Estimation of total brain PB and VPA concentrations revealed that the observed interactions between AGM and PB or VPA in the MES test were pharmacodynamic in nature because neither total brain PB, nor total brain VPA concentrations were altered after i.p. administration of AGM at 100 mg/kg. Moreover, none of the examined combinations of AGM (100 mg/kg) with CBZ, LTG, OXC, PB, PHT, TPM, and VPA (at their ED50 values from the MES test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no acute adverse effects in animals. In conclusion, one can ascertain that the selective potentiation of the antielectroshock action of PB and VPA by AGM, lack of any pharmacokinetic interactions between drugs and no acute adverse effects, make the combinations of AGM with PB or VPA of pivotal importance for epileptic patients. It seems that modulation of AGM concentration in the brain may occur favorable in further clinical practice.

Furosemide potentiates the anticonvulsant action of valproate in the mouse maximal electroshock seizure model

Accumulating evidence indicates that furosemide (FUR, a loop diuretic) exerts the anticonvulsant action in various in vitro and in vivo experiments. Therefore, the aim of this study was to assess the influence of FUR on the protective action of numerous conventional and newer antiepileptic drugs (carbamazepine [CBZ], lamotrigine [LTG], oxcarbazepine [OXC], phenobarbital [PB], topiramate [TPM] and valproate [VPA]) in the mouse maximal electroshock seizure (MES) model. Results indicate that FUR (up to 100mg/kg, i.p., 30 min before the test) neither altered the threshold for electroconvulsions nor protected the animals against MES-induced seizures in mice. FUR (100 mg/kg, i.p.) enhanced the anticonvulsant effects of VPA in the MES test by reducing its ED(50) value from 230.4 to 185.4 mg/kg (P<0.05). In contrast, FUR at 100 mg/kg had no significant effect on the antielectroshock action of the remaining drugs tested (CBZ, LTG, OXC, PB, and TPM) in mice. Estimation of free plasma and total brain VPA concentrations revealed that the observed interaction between FUR and VPA in the MES test was pharmacodynamic in nature because neither free plasma nor total brain VPA concentrations were altered after i.p. administration of FUR. In conclusion, one can ascertain that the selective potentiation of the antielectroshock action of VPA by FUR and lack of any pharmacokinetic interactions between drugs, make this combination of pivotal importance for epileptic patients treated with VPA and received FUR from other than epilepsy reasons.

Mirtazapine does not affect pentylenetetrazole- and maximal electroconvulsive shock-induced seizures in mice

Mirtazapine is an antidepressant exhibiting both noradrenergic and serotonergic activity. We have investigated the effects of mirtazapine on pentylenetetrazole (PTZ)- and maximal electroconvulsive shock (MES)-induced seizures in mice. Mirtazapine (1.25–20 mg/kg) or saline was administered, and locomotor activity was evaluated for 30 min. One hour after administration of mirtazapine (1.25–5 mg/kg) or saline, PTZ (80 mg/kg) was injected intraperitoneally into the mice. Immediately afterward, times of onset of the first myoclonic jerk (FMJ), generalized clonic seizures (GCS), and tonic extension (TE) were recorded. In the MES groups, we used the MES protocol to induce convulsions characterized by tonic hindlimb extension. Similarly, 1 h after mirtazapine or saline administration, an electroshock was evoked by ear-clip electrodes to induce convulsion. Mirtazapine, at 10 and 20 mg/kg, depressed locomotor activity. Doses of 1.25–5 mg/kg had no significant effect on the time of onset of FMJ, GCS, or TE induced by PTZ; on the duration of GCS and TE; or on the latency to reinstatement of the righting reflex after MES administration. Our results suggest that mirtazapine neither aggravates nor alleviates PTZ- or MES-induced seizures in mice.

1-Methyl-1,2,3,4-tetrahydroisoquinoline enhances the anticonvulsant action of carbamazepine and valproate in the mouse maximal electroshock seizure model

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ – an endogenous parkinsonism-preventing substance) administered intraperitoneally at a dose of 20 mg/kg considerably elevated the threshold for electroconvulsions in mice from 6.4 to 8.4 mA ( P < 0.05). In contrast, the agent administered at 5 and 10 mg/kg had no significant impact on the electroconvulsive threshold in mice. Moreover, 1-MeTHIQ (at a subthreshold dose of 10 mg/kg) potentiated the anticonvulsant action of valproate (VPA) against maximal electroshock (MES)-induced seizures in mice, reducing its median effective dose (ED 50) from 232 to 170 mg/kg ( P < 0.001). Similarly, 1-MeTHIQ (at 10 mg/kg) enhanced the antielectroshock activity of carbamazepine (CBZ) in mice, decreasing its ED 50 from 10.8 to 7.8 mg/kg ( P < 0.05). In contrast, 1-MeTHIQ (at 10 mg/kg) did not affect the anticonvulsant action of phenytoin and phenobarbital against MES-induced seizures in mice. The evaluation of acute neurotoxic effects of the studied antiepileptic drugs (AEDs) in combination with 1-MeTHIQ, as regards motor coordination impairment in the chimney test, revealed no significant changes in median toxic doses (TD 50) of conventional AEDs after systemic administration of 1-MeTHIQ (up to 10 mg/kg). Pharmacokinetic characterization of interactions between 1-MeTHIQ (10 mg/kg) and VPA (170 mg/kg) or CBZ (7.8 mg/kg) revealed no significant changes in total brain concentrations of CBZ and VPA, indicating that the observed enhancement of antiseizure effects of CBZ and VPA by 1-MeTHIQ was pharmacodynamic in nature. Based on our preclinical study, it may be concluded that 1-MeTHIQ exerts the anticonvulsant effects increasing the threshold for electroconvulsions and potentiating the antiseizure action of CBZ and VPA against maximal electroshock. The antiseizure properties of 1-MeTHIQ (an endogenous parkinsonism-preventing substance) and its exact physiological role in the brain need extensive examination in further neuropharmacological studies.

EFFECT OF PROPRANOLOL AND NIFEDIPINE ON MAXIMAL ELECTROSHOCK-INDUCED SEIZURES IN MICE: INDIVIDUALLY AND IN COMBINATION

A comparative effect of propranolol and nifedipine administered individually and in combination at graded dose levels; and that of phenytoin at 30 mg kg−1on maximal electroshock (MES)-induced seizure in mice was investigated. Propranolol in doses of 10 mg kg−1and 20 mg kg−1, and nifedipine in doses of 8 mg kg−1and 16 mg kg−1significantly modified MES activity. Propranolol (40 mg kg−1), and a combination of propranolol (20 mg kg−1) and nifedipine (8 mg kg−1), produced antiMES activity, which was comparable to that of phenytoin (30 mg kg−1). In mice treated with propranolol and nifedipine combination, the tonic flexor and tonic extensor phase ratios (F/E ratio) were significantly higher than individual drug responses. Our findings suggest that a combination of propranolol and nifedipine has either synergistic or an additive effect in controlling MES-induced seizures in mice.

The anticonvulsant activities of functionalized N-benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent

Recent studies have demonstrated that substituted N-benzyl 2-acetamidoacetamides provide significant protection against maximal electroshock (MES)-induced seizures in mice and rats. In this study, we investigated whether the 2-acetamido moiety was necessary for anticonvulsant activity. Ten derivatives of the known anticonvulsant, N-benzyl 2-acetamido-2-phenylacetamide were prepared in which the 2-acetamido group was replaced by hydrogen, methyl, oxygen, and halogen substituents. Evaluation of these compounds in the MES-induced seizure test demonstrated that both the hydroxy and the methoxy compounds provided full protection against MES-induced seizures in mice given ip at 100 mg/kg. Moreover, evaluation of the individual stereoisomers for the hydroxy compound showed that the principal activity resided in the ( R)-isomer. These findings demonstrated that the 2-acetamido substituent is important but not obligatory for the prevention of MES-induced seizures. Further supporting evidence was provided by comparing the pharmacological activities of N-benzyl 2,3-dimethoxypropionamide with N-benzyl 2-acetamido-3-methoxypropionamide. The ED 50 value for the former in the MES test was 30 mg/kg (ip), which compared favorably with phenobarbital (ED 50 = 22 mg/kg), but the ED 50 value for N-benzyl 2-acetamido-3-methoxypropionamide was 8.3 mg/kg.

Synthesis and anticonvulsant activities of alpha-heterocyclic alpha-acetamido-N-benzylacetamide derivatives.

Earlier studies showed that (R,S)-alpha-acetamido-N-benzylacetamides (2) containing a five- and six-membered aromatic or heteroaromatic group appended at the C(alpha) site displayed outstanding activity in the maximal electroshock-induced seizure (MES) test in mice. An expanded set of C(alpha)-heteroaromatic analogues of 2 have been prepared and evaluated. The observed findings extended the structure-activity relationships previously discerned for this novel class of anticonvulsants and have validated previous trends. The alpha-furan-2-yl (4), alpha-oxazol-2-yl (18), and alpha-thiazol-2-yl (19) alpha-acetamido-N-benzylacetamides afforded excellent protection against MES-induced seizures in mice. The ED50 and PI values for these adducts rivaled those reported for phenytoin. The outstanding properties provided by 4 led to an in-depth examination of the effect of structural modification at key sites within this compound on biological activity. The pharmacological data in this series indicated that stringent steric and electronic requirements existed for maximal activity and revealed the outstanding activity of (R)-(-)-alpha-acetamido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)aceta mide [(R)-30].