MES-induced Seizures Research Articles

Transplantation of inhibitory precursor cells from medial ganglionic eminence produces distinct responses in two different models of acute seizure induction.

Medial ganglionic eminence (MGE) is one of the sources of inhibitory interneurons during development. Following transplantation in postnatal developing brain, MGE cells can increase local inhibition suggesting a possible protection to GABAergic dysfunction in brain disorders, such as epilepsy. Since it has been shown that MGE-derived cells harvested as neurospheres are able to suppress seizures, it might be important to investigate whether these protective effects would change in different seizure models. Here, we used pentylenetetrazole-(PTZ) and maximal electroshock (MES)-induced seizure models to test whether the transplantation of MGE cells would increase the threshold to trigger acute seizures. When transplanted into the neocortex (layers 3-4) of neonatal mice (postnatal days 3-4), MGE cells were able to survive and were mainly found in piriform cortex, fimbria, and ventricular wall regions. Additionally, the number of GFP+ cells found in the brains of mice induced with PTZ and MES differed significantly and suggests proliferation and larger survival rate of MGE-transplanted cells after PTZ, but not MES-induced seizures. Following transplantation, there was a reduction in the number of animals presenting mild and severe seizures induced by PTZ. Furthermore, MGE-cell transplantation was able to increase threshold to seizures induced by PTZ, but was not able to prevent seizure spread induced by MES.

Evaluation of Brain Pharmacokinetic and Neuropharmacodynamic Attributes of an Antiepileptic Drug, Lacosamide, in Hepatic and Renal Impairment: Preclinical Evidence.

The knowledge of pharmacokinetic and pharmacodynamic properties of antiepileptic drugs is helpful in optimizing drug therapy for epilepsy. This study was designed to evaluate the pharmacokinetic and pharmacodynamic properties of lacosamide in experimentally induced hepatic and renal impairment in seizure animals. Hepatic or renal impairment was induced by injection of carbon tetrachloride or diclofenac sodium, respectively. After induction, the animals were administered a single dose of lacosamide. At different time points, maximal electroshock (MES) seizure recordings were made followed by isolation of plasma and brain samples for drug quantification and pharmacodynamic measurements. Our results showed a significant increase in the area under the curve of lacosamide in hepatic and renal impairment groups. Reduced clearance of lacosamide was observed in animals with renal impairment. Along with pharmacokinetic alterations, the changes in pharmacodynamic effects of lacosamide were also observed in all the groups. Lacosamide showed a significant protection against MES-induced seizures, oxidative stress, and neuroinflammatory cytokines. These findings revealed that experimentally induced hepatic or renal impairment could alter the pharmacokinetic as well as pharmacodynamic properties of lacosamide. Hence, these conditions may affect the safety and efficacy of lacosamide.

Early preclinical evaluation of dihydropyrimidin(thi)ones as potential anticonvulsant drug candidates

Although significant advances are occurring in epilepsy research, about 30% of epileptic patients are still inadequately controlled by standard drug therapy. For this reason, it continues to be important to develop new chemical entities through which epilepsy could be effectively controlled. In this study, the anticonvulsant activity of forty-two dihydropyrimidin(thi)ones was explored and their efficacy was evaluated in rodents against the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole tests. The results of preliminary pharmacological screening after intraperitoneal injection in mice revealed that twenty-four compounds showed protection in half or more of the animals tested in the MES seizure model, being nine of them active at the lowest dose tested (30mg/kg). Structurally, the most promising compounds (both urea and thiourea derivatives) presented smaller lateral chains and unsubstituted or para-substituted phenyl ring with a methyl group. Compounds 4, 5 and 11 also protected against MES-induced seizures in 50–75% of rats after oral administration at 30mg/kg. Moreover, the minimal motor and/or neurological impairment evaluated through the rotarod assay showed that around 52% of the compounds presented lower toxicity than the antiepileptic drugs lamotrigine, carbamazepine and phenytoin. In addition, the most active compounds did not show notable cytotoxicity in in vitro experiments conducted in several cell lines (relative cell proliferation higher than 50% at 30μM), which can be relevant due to the fact that the toxicity is a common problem of the available antiepileptic drugs. Furthermore, additional computational studies indicated that all compounds respected the Lipinski's rule of five, which, together with the data of efficacy and toxicity, make them attractive compounds to be developed in the future as potential anticonvulsant agents.

Design and Synthesis of 5-Substituted Benzo[d][1,3]dioxole Derivatives as Potent Anticonvulsant Agents.

A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Neurotoxicity was determined by rotarod test. In the preliminary screening, six compounds, 3a, 3c, 3d, and 4d-f, showed promising anticonvulsant activities in the MES model, and compounds 4c and 4d exhibited full protection against seizures at doses of 300 mg/kg in the scPTZ model. Among the synthesized compounds, 3c as the most active compound showed high protection against the MES-induced seizures with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice, thus providing compound 3c with a high protective index (TD50 /ED50 ) of 23.4 comparable to those of reference antiepileptic drugs.

Evaluation of the effect of volatile oil extract of Nigella sativa seeds on maximal electroshock-induced seizures in albino rats

Background: Epilepsy is one of the most common serious neurological disorders, responsible for substantial morbidity and mortality due to the seizures and the available medications. Natural products from folk remedies have contributed significantly in the discovery of modern drugs with novel structures and better safety and efficacy profiles. In this regard, one such plant is Nigella sativa. Aims and Objectives: (i) To evaluate the anticonvulsant activity of volatile oil extract of N. sativa seeds by maximal electroshock (MES)-induced seizure model of epilepsy in albino rats; (ii) To evaluate the influence of volatile oil extract of N. sativa seeds on the anticonvulsant activity of sodium valproate in albino rats. Materials and Methods: Male Albino rats (150-200 g) were randomly selected, from Central Animal Facility, Mysore Medical College and Research Institute, Mysore. The anticonvulsant activity was screened using MES-induced seizure model. Albino rats were divided into six groups of six rats each. Six groups were treated with gum acacia 0.5 ml (control group), sodium valproate 300 mg/kg (standard group), Groups 3, 4, and 5 were administered the test drug, volatile oil extract of N. sativa seeds at doses of 200, 400, and 600 mg/kg, respectively, and Group 6 was treated with the combination of test drug, volatile oil extract of N. sativa seeds 200 mg/kg and sodium valproate 150 mg/kg. All the drugs were dissolved in gum acacia and administered intraperitoneally 30 min prior to induction of seizures. Results: The volatile oil extract of N. sativa seeds showed the anticonvulsant activity in electroshock-induced seizure model at the dose of 400 and 600 mg/kg body weight and the potentiation of anticonvulsant activity of sodium valproate. The anticonvulsant activity of volatile oil of N. sativa seeds was less when compared to sodium valproate. Conclusions: The N. sativa seeds showed the anticonvulsant activity in MES-induced seizure model of epilepsy. This study showed that volatile oil of N. sativa seeds potentiated the effect of sodium valproate.

DESIGN AND SYNTHESIS OF 4-SUBSTITUTED QUINAZOLINE DERIVATIVES FOR THEIR ANTICONVULSANT AND CNS DEPRESSANT ACTIVITIES

<p><strong>Objective: </strong>The present work is designed to synthesise some isomeric new series of Quinazoline-4-one/4-thione derivatives, based on the pharmacophoric model of central nervous system (CNS) activity by structural modifications retaining the essential structural features for the activity and evaluated for their anticonvulsant and CNS depressant properties.</p><p><strong>Methods: </strong>A series of 7-chloro-3-[substituted (amino/phenylamino)]-2-phenyl quinazolin-4 (3H)-one/thione derivatives and 1-(7-chloro-4-oxo/-2-phenylquinazoline-3 (4H-yl)) substituted urea derivatives were prepared. The reaction scheme proceeds through the intermediate 7-chloro-2-phenyl-4H-benzo[d] [1, 3] oxazin-4-one. The structures of the newly synthesised compounds were characterized from infrared (IR), <sup>1</sup>H nuclear magnetic resonance (NMR) and mass spectra (m/z) and elemental analysis. The anti-convulsant and CNS depressant activity were investigated by maximum electroshock (MES) seizure test and porsolt’s behavioural despair test (forced swimming) respectively. The rota-rod test was performed to assess any probable changes in motor coordination induced by the test compounds.</p><p><strong>Results: </strong>The physicochemical and spectroscopic data clearly confirmed the synthesis of quinazoline derivatives with a common skeleton. The synthesised compounds were evaluated for their anticonvulsant and CNS depressant properties. Among them, six compounds <strong>(IIc, </strong>IIg, IIj, IIIc, IIIg, IIIj) exhibited a good activity profile in CNS depressant activity. Five compounds (IIc, IIg, IIj, IIIg, IIIh) showed protection against MES-induced seizures.</p><p><strong>Conclusion: </strong>The Quinazoline derivatives obtained from this research work indicates that the methyl/methoxy group in phenyl ring, amine and thiourea substitution at 3<sup>rd</sup> position of quinazoline derivatives are essential for CNS depressant activity as well as anticonvulsant activity. Compounds IIc, IIg, IIj, IIIc, IIIg, IIIj, and IIIh were found to be a potent compound which may be effective as a potential source for the development of CNS depressant and anti-convulsant drugs with lesser side effects</p>

Synthesis and potential anticonvulsant activity of new aryl sulfonyl semicarbazide derivatives

In the present study on the development of new anticonvulsants, twelve new aryl sulfonyl semicarbazide derivatives were synthesized and tested for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole screens. Their neurotoxicity was determined by the rotorod test. The most active compound 5i showed the MES-induced seizures with ED50 value of 7.3 mg/kg and TD50 value of 402.3 mg/kg after intraperitoneally injection to mice, which provided compound 5i with a protective index (TD50/ED50) of 55.1 in the MES test.

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Background/Aims: To characterize the anticonvulsant effects of a combination of 3 antiepileptic drugs (AEDs; i.e. carbamazepine (CBZ), phenobarbital (PB) and topiramate (TPM)) at the fixed-ratio of 1:1:1 in the mouse maximal electroshock (MES)-induced seizure model. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to analyze the 3-drug combination. Results: In the mouse MES model, all the studied AEDs (i.e. CBZ, PB and TPM) administered singly had their DRRCs parallel to each other. With type I isobolography for parallel DRRCs, a combination of CBZ, PB and TPM at the fixed-ratio of 1:1:1 exerted supra-additive (synergistic) interaction in the mouse MES model. Conclusions: Synergistic interaction among CBZ, PB and TPM at the fixed-ratio of 1:1:1 against MES-induced seizures is worthy of consideration in further clinical settings. All detailed calculations required to perform type I isobolographic analysis for the 3-drug combination were presented.

A role for ATP-sensitive potassium channels in the anticonvulsant effects of triamterene in mice

There are reports indicating that diuretics including chlorothiazide, furosemide, ethacrynic acid, amiloride and bumetanide can have anticonvulsant properties. Intracellular acidification appears to be a mechanism for the anticonvulsant action of some diuretics. This study was conducted to investigate whether or not triamterene, a K+-sparing diuretic, can generate protection against seizures induced by intravenous or intraperitoneal pentylenetetrazole (PTZ) models. And to see if, triamterene can withstand maximal electroshock seizure (MES) in mice. We also investigated to see if there is any connection between triamterene's anti-seizure effect and ATP-sensitive K+ (KATP) channels. Five days triamterene oral administration (10, 20 and 40mg/kg), significantly increased clonic seizure threshold which was induced by intravenous pentylenetetrazole. Triamterene (10, 20 and 40mg/kg) treatment also increased the latency of clonic seizure and decreased its frequency in intraperitoneal PTZ model. Administration of triamterene (20mg/kg) also decreased the incidence of tonic seizure in MES-induced seizure. Co-administration of a KATP sensitive channel blocker, glibenclamide, in the 6th day, 60min before intravenous PTZ blocked triamterene's anticonvulsant effect. A KATP sensitive channel opener, diazoxide, enhanced triamterene's anti-seizure effect in both intravenous PTZ or MES seizure models. At the end, triamterene exerts anticonvulsant effect in 3 seizure models of mice including intravenous PTZ, intraperitoneal PTZ and MES. The anti-seizure effect of triamterene probably is induced through KATP channels.

The potential anticonvulsant activity of the ethanolic extracts of Achillea nobilis and Momordica charantia in rats

Context: Currently available antiepileptic drugs have debilitating adverse effects. Natural products and plants already used in traditional medicine can be a good place to start in the search for safer and more effective options. Aims: To investigate the anticonvulsant potential of Achillea nobilis and Momordica charantia extracts in maximal electroshock (MES), as well as pentylenetetrazole (PTZ)- and strychnine nitrate (STN)- induced seizure models in rats. Methods: For each model, eight groups of 21-day-old male Albino rats were used. The 1st group was kept as control, 2nd as standard (diazepam, 7.5 mg/kg); 3rd - 5th treated with A. nobilis (100, 200 and 300 mg/kg); and 6th - 8th administered M. charantia (100, 200 and 300 mg/kg). After 30 min, rats were exposed to a shock of 150 mA by a convulsiometer, via ear electrodes for 2 s (in MES test) or sc injection of PTZ (85 mg/kg) or STN (2.5 mg/kg). Results: A. nobilis and M. charantia extracts (200 and 300 mg/kg) demonstrated dose-dependent anticonvulsant effect against MES-induced seizures. In the PTZ induced convulsion, A. nobilis and M. charantia (200 and 300 mg/kg) significantly slowed the commencement of convulsions and minimized the duration of seizures. A. nobilis (300 mg/kg) showed 60% protection in rats against STN induced seizures. In contrast, A. nobilis (100 and 200 mg/kg) and M. charantia (100, 200 and 300 mg/kg) showed no significant protection against STN-induced seizures in rats. Conclusions: The results of the present study suggest that both extracts exhibited marked anticonvulsant activities.

Evaluation of anticonvulsant activity of polyherbal formulation based on ayurvedic formulation Brihad Panchagavya Ghrita

Background: The aim of the present study was to develop a polyherbal formulation for epilepsy. Present polyherbal formulation (PHF) (containing Operculina turpethum (L.) Silva Manso, Mimosa pudica L., Uraria picta (Jacq.) DC., Cajanus cajan (L.) Millsp, and Lawsonia inermis L.) is based on an ayurvedic formulation Brihad Panchagavya Ghrita indicated for epilepsy. Materials and Methods: To establish the scientific basis of mechanism, we examined the effects of methanolic extract of PHF (100, 200, and 400 mg/kg, p.o.) on maximal electric shock (MES), pentylenetetrazol (PTZ), and isoniazid (INH)-induced convulsions as well as gamma-aminobutyric acid (GABA)-glutamate level in the brain tissues in PTZ-induced seizure model. Phenytoin (25 mg/kg, i.p.) for MES-induced seizure and diazepam (2 mg/kg, i.p.) for PTZ and INH-induced epilepsy were used as reference drugs, respectively. Results: The extract showed no toxicity and significantly prolonged the onset and reduced the duration of the seizures induced by MES. Phenytoin (25 mg/kg, i.p.) completely inhibited the seizures in this model. Similarly, in the seizures induced by PTZ and INH, the extract also prolonged the onset and reduced the duration of the seizures though not in a dose-dependent manner. Diazepam also inhibits the PTZ and INH-induced seizures. The plant extract however showed a significant anticonvulsant activity at 400 mg/kg in comparison with diazepam. The extract also attenuates the chemical (PTZ) induce oxidative stress in the brain. Moreover, the extract (400 mg/kg) also significantly decreases the GABA-transaminase enzyme activity in PTZ model. The PHF was also found to be capable in reversing the INH-induced decline in GABA level and increase in glutamate level in the brain. Conclusions: The results obtained from this work suggest that PHF has anticonvulsant activity, and this supports the use of the formulation traditionally in the treatment of convulsions.

Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats

It has become clear that histamine H3 receptors (H3Rs) are implicated in modulating epilepsy and memory in laboratory animals. The new non-imidazole H3R antagonist DL77 has excellent selectivity profile and shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 values of 2.1 ± 0.2 mg/kg and 8.4 ± 1.3 [nM], respectively. In the present study, the anticonvulsant effects of DL77 on maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced seizure models were investigated. Moreover, the procognitive properties of DL77 were tested on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in male Wistar rats. The results indicate that DL77 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently reduced MES-induced seizure duration, whereas no protection was observed in PTZ- or STR-induced seizures. Importantly, the protective action observed for DL77 in MES-induced seizure was comparable to that of the reference antiepileptic drug (AED) phenytoin (PHT), and was also reversed when rats were pretreated with the CNS penetrant pyrilamine (PYR) (10 mg/kg, i.p.), or with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg, i.p.). Furthermore, the procognitive studies indicate that acute pre-training systemic administration of DL77 (2.5 mg/kg, i.p.) facilitated acquisition, whereas pre-testing acute administration of DL77 (5 and 10 mg/kg, i.p.) improved retrieval. Interestingly, the procognitive effect of DL77 on retrieval was completely abrogated when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL) but not the centrally acting H1R antagonist PYR, indicating that histaminergic pathways through activation of H2Rs appear to be participating in neuronal circuits involved in retrieval processes. Taken together, our results show that DL77 demonstrates anticonvulsant properties in the MES-induced seizure model and improves cognitive performance through actions on different memory stages. Therefore, H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacological target to tackle cognitive problems associated with the chronic use of antiepileptic drugs.This article is part of the Special Issue entitled ‘Histamine Receptors’.

Synthesis and potential anticonvulsant activity of new 5,5-cyclopropanespirohydantoin derivatives

In this study, sixteen new 5,5-cyclopropanespirohydantoin derivatives were synthesized and tested for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole screens. Their neurotoxicity was determined by the rotarod test. Two compounds 7f and 7n showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 7f showed the MES-induced seizures with ED50 value of 8.5 mg/kg and TD50 value of 381.7 mg/kg after intraperitoneally injection to mice, which provided compound 7f with a protective index (TD50/ED50) of 44.9 in the MES test.

Anticonvulsant mechanisms of piperine, a piperidine alkaloid

Piperine, a natural compound isolated from the fruits of Piper, is known to modulate several neurotransmitter systems such as serotonin, norepinephrine, and GABA, all of which have been linked to the development of convulsions. Fruits of Piper species have been suggested as means for managing seizure disorders. The present study was designed to elucidate the anticonvulsant effect of piperine and its mechanisms of action using in-silico, in-vivo and in-vitro techniques.PASS software was used to determine its possible activity and mechanisms. Furthermore the latency for development of convulsions and mortality rate was recorded in different experimental mouse models of epilepsy (pentylenetetrazole, maximal electroshock, NMDA, picrotoxin, bicuculline, BAYK-8644, strychnine-induced convulsions) after administration of various doses of piperine (5, 10 and 20 mg/kg, i.p.). Finally, the effect of piperine on Na+ and Ca2+ channels were evaluated using the whole cell patch clamp techniqueOur results revealed that piperine decreased mortality in the MES-induced seizure model. Moreover, piperine (10 mg/kg) delayed the onset of tonic clonic convulsions in the pentylenetetrazole test and reduced associated mortality. Furthermore, an anticonvulsant dose of piperine also delayed the onset of tonic clonic seizures in strychnine, picrotoxin and BAY K-8644. Complete protection against mortality was observed in BAYK-8644 induced convulsions. Finally, whole cell patch clamp analysis suggested an inhibitory effect of piperine on Na+ channels. Together, our data suggest Na+ channel antagonist activity as a contributor to the complex anticonvulsant mechanisms of piperine.

Low-frequency stimulation of the external globus palladium produces anti-epileptogenic and anti-ictogenic actions in rats.

To investigate the anti-epileptic effects of deep brain stimulation targeting the external globus palladium (GPe) in rats. For inducing amygdala kindling and deep brain stimulation, bipolar stainless-steel electrodes were implanted in SD rats into right basolateral amygdala and right GPe, respectively. The effects of deep brain stimulation were evaluated in the amygdala kindling model, maximal electroshock model (MES) and pentylenetetrazole (PTZ) model. Moreover, the background EEGs in the amygdala and GPe were recorded. Low-frequency stimulation (0.1 ms, 1 Hz, 15 min) at the GPe slowed the progression of seizure stages and shortened the after-discharge duration (ADD) during kindling acquisition. Furthermore, low-frequency stimulation significantly decreased the incidence of generalized seizures, suppressed the average stage, and shortened the cumulative ADD and generalized seizure duration in fully kindled rats. In addition, low-frequency stimulation significantly suppressed the average stage of MES-induced seizures and increased the latency to generalized seizures in the PTZ model. High-frequency stimulation (0.1 ms, 130 Hz, 5 min) at the GPe had no anti-epileptic effect and even aggravated epileptogenesis induced by amygdala kindling. EEG analysis showed that low-frequency stimulation at the GPe reversed the increase in delta power, whereas high-frequency stimulation at the GPe had no such effect. Low-frequency stimulation, but not high-frequency stimulation, at the GPe exerts therapeutic effect on temporal lobe epilepsy and tonic-colonic generalized seizures, which may be due to interference with delta rhythms. The results suggest that modulation of GPe activity using low-frequency stimulation or drugs may be a promising epilepsy treatment.

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.

Design, synthesis and pharmacological evaluation of novel N-(2-(1, 1-dimethyl-5, 7-dioxo-4, 6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives as potential anticonvulsant agents

A series of new N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives (8a-i) and ethyl 2,2-dimethyl-1-(3-(2-(sulfonamido)ethyl)ureido) cyclopropanecarbox-ylate derivatives (9a-i) were designed, synthesized and evaluated for their anticonvulsant activities using maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4-fluoroben- zenesulfonamide (8f) and N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4- methylbenzenesulfonamide (8e) have shown promising anticonvulsant activities in MES model. The most active compound 8f has shown the MES-induced seizures with ED50 value of 28.05 mg/kg and TD50 value of 561 mg/kg after intraperitoneal injection to mice, which provided compound 8f with a protective index (TD50/ED50) of 20 in the MES test. Further, rotarod toxicity method was used to study the acute neurotoxicity profile of selected compounds.

Anticonvulsant activity of 1,2,4-triazine derivatives with pyridyl side chain: synthesis, biological, and computational study

A series of 5,6-bisaryl-1,2,4-triazine-3-thiol-substituted derivatives were synthesized by condensation of 1,2-diketones and thiosemicarbazide under microwave irradiations and subsequent alkylation of thiol group by chloromethylpyridinium chloride. Evaluation of anticonvulsant activity of compounds was performed by maximal electroshock and pentylenetetrazole-induced seizures tests. In order to evaluate their neuroprotective potential, the ability of compounds to inhibit soybean 15-lipoxygenase was also assessed. Further molecular modeling and docking study on Na+ channel and GABAA receptor was performed to elucidate their mechanisms of action and necessary interactions in the active site. Compounds 2c and 2d with bis(4-bromophenyl) and pyridyl substituents showed highest protection up to 70 and 80 % in PTZ and MES-induced seizures, respectively, compared to the control group. Molecular docking study revealed their possible antiseizure mechanism of action through GABAA receptor, and in silico assessment of their BBB permeability indicated them as CNS active agents.

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.

Anticonvulsant activity of the aqueous extract of &lt;i&gt;Allium cepa&lt;/i&gt; L. (Amaryllidaceae) in rats and mice

The aqueous extract of Allium cepa (ACE) has been reported to be effective in the treatment of convulsion. We therefore investigated its effect on seizures induced by maximal electroshock stimulation (MES) andpentylenetetrazole (PTZ) in rats and mice. The preliminary phytochemical constituents were also elucidated. The extract contained tannins, flavonoids, cardiac glycosides, reducing sugars, saponins and alkaloids. Anthraquinones, steroids and terpenes were absent. In the electrically-induced seizure, ACE significantly (p&lt; 0.01) prolonged the onset of tonic convulsion at all doses. It also reduced the duration of the tonic convulsion at all doses but it is only significant at 50mg/kg (p&lt; 0.02), 200mg/kg (p&lt; 0.03) and 400mg/kg (p&lt; 0.004). It was reduced from 3.295 ± 0.448s (control) to 1.172 ± 0.837s (50mg/kg); 1.62 ± 0.670s (200mg/kg) and 0.832 ± 0.376s (400mg/kg). In the PTZinduced seizure ACE prolonged the onset of tonic convulsion at 50mg/kg and 200mg/kg dose but it wasinsignificant. It was increased from 3.469 ± 1.335 min (control) to 3. 999 ± 1.658 min (50mg/kg) and 4.261 ± 0.740 min (200mg/kg). It also delayed the time it took for the mice to die at 50mg/kg and 200mg/kg, although not significantly. It is concluded that Allium cepa extract has an anticonvulsant effect especially in MES-induced seizure and could serve as a good alternative for the treatment of convulsion. This observation explains, at least in part, the basis for its use by herbalists for the treatment of convulsion.Keywords: Maximal electroshock stimulation; Pentylenetetrazole; Anticonvulsant; Allium cepa