Maximal Electroshock-induced Seizure Test Research Articles

Psychomotor Seizure Screening and in vitro Neuroprotection Assay of Hydrazones Derived from 2-Acetyl Thiophene

Hydrazone core is a versatile structural linker for the development of various classes of antiepileptic agents. The aim of this study was to investigate the anticonvulsant activity of thiophene based hydrazones according to the antiepileptic drug development program protocol. The maximal electroshock-induced seizure and 6 Hz "Psychomotor" seizure test models in mice were performed. Additionally, the active compounds in the screening test were subsequently subjected to the maximal electroshock-induced seizure test that allowed determination of their median effective doses and median toxic doses. The most active compound was also subjected to the In vitro Hippocampal slice culture neuroprotection assay. Among the synthesized compounds, 1-(thiophen-2-yl) ethylidene] hydrazine carboxamides (THb) and 1-(thiophen-2-yl) ethylidene] hydrazine carbothioamide (THc) showed a broad-spectrum anticonvulsant activity since they were active in both maximal electroshock-induced seizure and 6Hz-Psychomotor induced seizure models with no neurotoxicity. In the mice maximal electroshock-induced seizure screen, compound THb gave an ED50 of 11.8 mg/kg and a TD50 of 39.47 mg/kg, resulting in a good protection index (PI), that is, TD50/ED50, of 3.3 when compared to Phenobarbital and Valproate. THb (100μM) was also found to be effectively suppressing network hyperexcitability in the in vitro mEC-HC spontaneous bursting model, as determined by effects on spontaneous burst activity and duration. The suggested pharmacophore model for lead compounds from thiophene based hydrazones is explained by the hydrophobic domain-thiophene, electron donor-imine and hydrogen bonding domain-carboxamide or carbothioamide unit.

Effects of xanthotoxin on the anticonvulsant action of various second-generation antiepileptic drugs in the maximal electroshock-induced seizure test in mice

Effects of xanthotoxin on the anticonvulsant action of various second-generation antiepileptic drugs in the maximal electroshock-induced seizure test in mice

Effect of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate in the maximal electroshock-induced seizure test in mice

Effect of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate in the maximal electroshock-induced seizure test in mice

Isobolographic analysis of interactions for selected three-drug combinations of antiepileptic drugs in the maximal electroshock-induced seizure test in mice

Isobolographic analysis of interactions for selected three-drug combinations of antiepileptic drugs in the maximal electroshock-induced seizure test in mice

Assessment of the effect of dihydroartemisinin-sodium valproate combination on some behavioural activities in mice

Co-morbidity inevitably warrant occurrence of polypharmacy that may result in interactions or modification of either the therapeutic or toxic effect of any of the drugs employed. Malaria and epilepsy have been known to occur concurrently as such may necessitate the co-administration of two or more drugs. This study evaluated the effect of dihydroartemisinin-valproate combination on some behavioral activities related to central nervous system. The study was conducted using animal models as follows: maximal electroshock-induced seizures test in mice, diazepam-induced sleep in mice and mouse beam walking test for motor coordination deficit. Generally, the results showed that there were no statistical significant effects in the test models. Therefore, dihydroartemisinin did not significantly influence the protective effect of sodium valproate in convulsion; and did not significantly cause sedation in animals. Hence, the result of this study suggests that dihydroartemisinin-sodium valproate combination could be considered safe in seizures condition.Keywords: Dihydroartemisinin, Polypharmacy, Valproate, Drugs, Epilepsy

Determination of 5-(3-Chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione in Mouse Brain Tissue by Microwave-Assisted Extraction and High-Performance Liquid Chromatography with Fluorescence Detection

A sensitive and selective method was developed for the determination of 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315), an antiepileptic compound, in the tissue homogenate of mouse brains by microwave-assisted extraction and high performance liquid chromatography with fluorescence detection by use of an external standard. The analyses were performed on a C18 column using a mobile phase consisting of 60% acetonitrile in water. Fluorescence detection was performed at an excitation wavelength of 263 nm and an emission wavelength of 411 nm. The method provided a high extraction yield with recoveries exceeding 90%. The precision values expressed by intra- and inter-day relative standard deviations were lower than 5%. The validated procedure was employed to develop a brain concentration profile after intraperitoneal administration of a single oral dose equal to 300 mg per kg of body weight. The time to the maximum anticonvulsant action of TP-315 in a mouse maximal electroshock-induced seizure test was 30 min after administration.

Influence of WIN 55,212-2 on the anticonvulsant and acute neurotoxic potential of clobazam and lacosamide in the maximal electroshock-induced seizure model and chimney test in mice

The influence of WIN 55,212-2 mesylate (WIN) on the anticonvulsant activity and acute neurotoxic potential of clobazam (CLB) and lacosamide (LCM) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice. indicate that WIN administered intraperitoneally, at doses of 2.5 and 5 mg/kg significantly enhanced the anticonvulsant action of CLB in the MES test by reducing its median effective dose (ED50) from 20.80 mg/kg to 12.05 mg/kg (P<0.05), and 8.22 mg/kg (P<0.001), respectively. In contrast, WIN (1.25 mg/kg) did not significantly potentiate the anticonvulsant activity of CLB against MES-induced seizures. Similarly, WIN at doses of 1.25, 2.5 and 5 mg/kg had no significant impact on the anticonvulsant action of LCM in the MES test. On the other hand, WIN (5 mg/kg) had no impact on the acute neurotoxic effects of CLB and LCM in the chimney test and the median toxic doses (TD50) for CLB and LCM were almost unchanged. Thus, WIN (5 mg/kg) elevated the protective index values for CLB (from 1.41 to 3.07) and LCM (from 3.60 to 4.91). In conclusion, WIN potentiates suppression of tonic-clonic seizures produced by CLB in the mouse MES model, without affecting acute neurotoxic adverse effects of CLB in the chimney test in mice, which is favorable from a preclinical point of view.

SYNTHESIS AND ANTICONVULSANT ACTIVITY OF 6-IODO PHTHALAZINEDIONE DERIVATIVES

A series of phthalazinedione bearing substituted sulfonamide moiety acetanilide esters hydrazide and oxadiazole derivatives (3a-f ),(4a-g),(5a-d) , (6), (7), (8), (9a-d) was synthesized in good yield and evaluated for their possible anticonvulsant activity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their anticonvulsant activity was evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. All the tested compounds showed considerable anticonvulsant activity in at least one of the tested compounds exhibited moderate anticonvulsant activity in both MES and PTZ tests. From these results, phthalazinedione bearing chloroacetyl benzene sulfonamide (3a-f-), acetanilide(4a-g) ester (5a-d), hydrazide (6), oxadiazole (7) and ester (9a-d) derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

Purification and anticonvulsant activity of xanthotoxin (8-methoxypsoralen)

AbstractThe aim of the present study was to determine the anticonvulsant effects of xanthotoxin (8-methoxypsoralen) isolated from the fruit of Pastinaca sativa L. This plant is used in European traditional medicine, including Poland. For this purpose, high-performance counter-current chromatography was used. Different solvent systems, mixtures of n-heptane, ethyl acetate, methanol and water were tested in order to calculate partition coefficients. Finally, a mixture with the ratio of 1:1:1:1 (v/v/v/v), giving the K value = 0.92, was chosen as optimal. A rapid scale-up process from analytical to preparative was developed. Evaluation of the anticonvulsant action of xanthotoxin in the mouse maximal electroshock-induced seizure test revealed that it produced a clear-cut anticonvulsant action in mice, and the experimentally-derived median effective doses (ED50 values) ranged between 219 and 252 mg kg−1.

Synthesis, characterization and preliminary anticonvulsant evaluation of some 4-alkyl-1,2,4-triazoles

Designed and synthesized 4-alkyl-1,2,4-triazole-3-thione derivatives showed significant anticonvulsant activity, determined in the maximal electroshock-induced seizure (MES) test. The chemical structure of all new compounds was confirmed by spectral methods (1H NMR, 13C NMR, IR, MS). A sensitive and selective method was elaborated for the determination of the anticonvulsant compounds levels in mice brain tissue, based on HPLC with diode array detector (DAD). Chromatographic tests showed that lack of anticonvulsant effect of two derivatives (15, 16) with long alkyl chains at N-4 position of the 1,2,4-triazole ring was due to the inability to cross the blood–brain barrier (BBB).

Some Novel Anticonvulsant Agents Derived from Phthalazinedione

A series of phthalazinedione bearing substituted oxadiazole moiety derivatives X(1-7) were synthesized in good yield and evaluated for their possible anticonvulsant activity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. All the tested compounds showed considerable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results,[3-)2-Alkoxycarbonylmethylthioxadiozol-5-yl)methyl -6-Iodophthalazine - 1,4- (2H,3H)-1,4-dion] (X1-7) derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice. 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, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED(50) values) from 23.25mg/kg to 16.82 mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7 mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED(50) value from 259.3mg/kg to 210.6 mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED(50) values from the maximal electroshock-induced seizure 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 possible acute adverse effects in animals. In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.

Synthesis, characterization, and pharmacological evaluation of new GABA analogs as potent anticonvulsant agents

A series of new γ-aminobutyric acid (GABA) derivatives was obtained from 4-(1,3-dioxoisoindolin-2-yl)butanoic acid by coupling it with various substituted amines by using DCC as coupling reagent. The compound 3 was synthesized by treating GABA and phthalimide at high temperature under anhydrous conditions. All the synthesized compounds were confirmed and characterized by using various spectral technique like (IR, 1H NMR, 13C NMR, and mass spectroscopy) studies. Anticonvulsant evaluations of all the synthesized compounds were done by using various seizures models like maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests at a dose of 30, 100, and 300 mg/kg body weight and anticonvulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. The compound 4a 4-(1,3-dioxoisoindolin-2-yl)-N-phenylbutanamide displayed weak anticonvulsant activity in MES test at a dose of 300 mg/kg. Analogs 4d, 4h, and 4m displayed promising activity in scPTZ seizures model. Most of the synthesized compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model. Among all the tested compounds, 4h 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl)butanamide showed protection in various seizures model except in the scSTY model, while analog 4d was found to be the most potent compound in scPTZ model showing protection at a dose of 30 mg/kg. Further all the compounds exhibited lesser neurotoxicity compared with standard drug. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.

Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: a comparative study

The aim of this study was to determine and compare the anticonvulsant activities of four natural furanocoumarins [bergapten (5-methoxypsoralen), imperatorin (8-isopentenyloxypsoralen), oxypeucedanin (5-epoxy-isopentenyloxypsoralen) and xanthotoxin (8-methoxypsoralen)] in the maximal electroshock-induced seizure test in mice. The anticonvulsant effects of bergapten, imperatorin, oxypeucedanin, and xanthotoxin were evaluated at 15, 30, 60 and 120min after their systemic (intraperitoneal) administration. Tonic hind limb extension (seizure activity) was evoked in adult albino Swiss mice by a current (sine-wave, 25 mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. The time courses of protection by bergapten, imperatorin, oxypeucedanin and xanthotoxin against maximal electroshock-induced seizures revealed that 300mg/kg imperatorin and xanthotoxin (C-8 substituted derivatives of psoralen) exerted strong anticonvulsant activity, whereas 300mg/kg bergapten and oxypeucedanin (C-5 substituted derivatives of psoralen) did not produce any anticonvulsant activity in this model. In conclusion, imperatorin and xanthotoxin protected the animals against maximal electroshock-induced seizures, whereas bergapten and oxypeucedanin, despite their chemical and structural similarities to xanthotoxin and imperatorin, exerted no anticonvulsant activity in this seizure test.

Isobolographic analysis of interactions between 1-methyl-1,2,3,4-tetrahydroisoquinoline and four conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

The anticonvulsant activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ — an endogenous parkinsonism-preventing substance) administered alone and in combination with four conventional antiepileptic drugs (carbamazepine, phenytoin, phenobarbital and valproate) was determined in the mouse maximal electroshock-induced seizure model. The types of interactions of MeTHIQ with the antiepileptic drugs were characterized using isobolographic analysis. The isobolographic analysis revealed that the combination of MeTHIQ with phenobarbital at the fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction in the maximal electroshock-induced seizure test. In contrast, the combinations of MeTHIQ with carbamazepine, phenytoin and valproate exerted additive interaction for all three fixed-ratios (1:3, 1:1 and 3:1) tested in the maximal electroshock-induced seizure test. In conclusion, MeTHIQ produces a clear-cut anticonvulsant effect in the maximal electroshock-induced seizure test in mice. The supra-additive interaction of MeTHIQ with phenobarbital against maximal electroshock-induced seizures makes their combination of pivotal importance from a clinical viewpoint.

Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione derivatives as novel broad spectrum anticonvulsants

Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide and N-CO-C-N group in their molecule were designed and synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. Almost all the designed compounds except 1c and 1f showed comparable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results, 6-amino-1,4-oxazepane-3,5-dione derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

Newer GABA derivatives for the treatment of epilepsy including febrile seizures: A bioisosteric approach

The present study aims at design and synthesis of newer γ-aminobutyric acid (GABA) derivatives with the combination of thiosemicarbazone and GABA pharmacophores in order to develop newer anticonvulsants. The reported compounds were designed as bioisosteric analogues of GABA semicarbazones. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. A model involving 22-day old rat pups was also employed to further screen the effects of the test compounds against hyperthermia-induced febrile seizures. Only compounds 1 and 11 were found to be active in the MES test. Most of the compounds were found to be effective in the scPIC and febrile seizure models and very few compounds showed protection in scPTZ and scSTY models. This is the first report on these new GABA derivatives effective in the treatment of febrile seizures.

Design and synthesis of anticonvulsants from a combined phthalimide–GABA–anilide and hydrazone pharmacophore

Two series of pharmacophoric hybrids of phthalimide–GABA–anilides/hydrazones were designed and synthesized and evaluated for their anticonvulsant and neurotoxic properties. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests. All of the compounds were ineffective in the MES test. Most of the compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model.

Study of anticonvulsant effect of citronellol, a monoterpene alcohol, in rodents

Citronellol is one monoterpene alcohol, which is present in the essential oils of various aromatic plant species. This study evaluated the neuroprotective activity of citronellol on pentylenetetrazol- and picrotoxin-induced convulsions and maximal electroshock-induced seizures in mice. Administration of citronellol significantly reduced the number of animals of convulsion induced by pentylenetetrazol and eliminated the extensor reflex of maximal electroshock-induced seizures test in about 80% of the experimental animals. In addition, administration of citronellol showed protection in the pentylenetetrazol and picrotoxin tests by increasing the latency of clonic seizures. We also investigated the effect of citronellol in the rat isolated nerve using the single sucrose-gap technique. We showed that the amplitude of the compound action potential decreased more than 90% when the monoterpene was incubated for 30 min at 6.4 mM and we did not verify any effect on the repolarization of the compound action potential. Taken together, our results demonstrated an anticonvulsant activity of the citronellol that could be, at least in part, explained by the diminution of the action potential amplitude.

2-Phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice

This study examined the effect of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent and selective inhibitor of glutamate carboxypeptidase II (GCP II), an enzyme releasing glutamate and N-acetyl-aspartate from synaptical terminals, on the electroconvulsive threshold in mice. Moreover, the influence of 2-PMPA on the anticonvulsant activities of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was evaluated in the maximal electroshock-induced seizure test in mice. Results indicated that 2-PMPA (at a dose range of 50–200 mg/kg, i.p.) raised the electroconvulsive threshold in mice dose-dependently. Linear regression analysis of dose–response relationship between the doses of 2-PMPA and their corresponding threshold values allowed the calculation of threshold increasing dose by 20% (TID 20), which was 109.2 mg/kg. Moreover, 2-PMPA administered i.p. at a constant dose of 150 mg/kg (the dose increasing the threshold for electroconvulsions) enhanced significantly the anticonvulsant action of valproate, by reducing its median effective dose (ED 50) from 281.4 to 230.1 mg/kg ( P < 0.05). In contrast, 2-PMPA at the lower dose of 100 mg/kg (i.p.) had no impact on the antiseizure activity of valproate in the maximal electroshock-induced seizure test. Likewise, 2-PMPA at 100 and 150 mg/kg did not affect the antiseizure action of carbamazepine, phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Additionally, none of the combinations investigated between 2-PMPA (150 mg/kg, i.p.) and carbamazepine, phenobarbital, phenytoin and valproate (at their ED 50 values) produced motor coordination impairment in the chimney test. Pharmacokinetic evaluation of interaction between 2-PMPA and valproate revealed that 2-PMPA at 150 mg/kg selectively increased total brain concentrations of valproate, remaining simultaneously without any effect on free plasma concentrations of valproate, indicating a pharmacokinetic nature of observed interaction in the maximal electroshock-induced seizures in mice. Based on our preclinical data, it may be concluded that 2-PMPA possesses a seizure modulating property by increasing the electroconvulsive threshold. The reduction of glutamate neurotransmission in the brain, as a consequence of inhibition of GCP II activity by 2-PMPA, was however insufficient to enhance the anticonvulsant activity of conventional antiepileptic drugs, except for valproate, whose antiseizure action against maximal electroconvulsions was potentiated by 2-PMPA. Unfortunately, the favourable interaction between 2-PMPA and valproate was associated with a pharmacokinetic increase in total brain valproate concentrations.