The anticonvulsant spectrum of the original promising anticonvulsant N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide was studied. The compound had a pronounced anticonvulsant effect, significantly reducing the mortality of mice in models of seizures induced by pentylenetetrazole, picrotoxin, strychnine, and caffeine. In the thiosemicarbazideinduced seizure model, the test compound did not reduce mortality. The obtained results indicated that the mechanism of anticonvulsant action involved GABA-ergic (effective in models of pentylenetetrazole and picrotoxin-induced seizures), glycinergic (efficiency in the strychnine model of paroxysms), and adenosinergic (effectiveness in the model of caffeine induced seizures). Molecular docking of a promising anticonvulsant to anticonvulsant biotargets follow the mechanisms of chemo-induced seizures, namely GABA, glycine, and adenosine receptors type A2A, GABAAT, and BCAT enzymes. The conformity between in vivo and in silico studies results was revealed.

• Klíčová slova
• A2A receptor, GABA receptor, Gly receptor, acetamide, anticonvulsant effect, docking, dose, dose of biotin, quinazoline,
• MeSH
• acetamidy farmakologie   MeSH
• akční spektrum MeSH
• antikonvulziva * farmakologie   MeSH
• GABA MeSH
• kofein MeSH
• myši MeSH
• pentylentetrazol * MeSH
• pikrotoxin MeSH
• simulace molekulového dockingu MeSH
• strychnin MeSH
• záchvaty chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetamide MeSH Prohlížeč
• acetamidy MeSH
• antikonvulziva * MeSH
• GABA MeSH
• kofein MeSH
• pentylentetrazol * MeSH
• pikrotoxin MeSH
• strychnin MeSH

The prevalence of epilepsy in the world population together with a high percentage of patients resistant to existing antiepileptic drugs (AEDs) stimulates the constant search for new approaches to the treatment of the disease. Previously a significant anticonvulsant potential of cardiac glycoside digoxin has been verified by enhancing a weak activity of AEDs in low doses under screening models of seizures induced by pentylenetetrazole and maximal electroshock. The aim of the present study is to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant activity of valproate, levetiracetam, and topiramate in models of primary generalized seizures with different neurochemical mechanisms. A total of 264 random-bred male albino mice have been used. AEDs were administered 30 min before seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate - at doses of 300 and 150 mg/kg; levetiracetam - at doses of 100 and 50 mg/kg. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10-15 min before seizure induction. Picrotoxin (aqueous solution 2.5 mg/kg, subcutaneously), thiosemicarbazide (aqueous solution 25 mg/kg, intraperitoneally), strychnine (aqueous solution 1.2 mg/kg, subcutaneously), camphor (oil solution 1000 mg/kg, intraperitoneally) have been used as convulsive agents for seizure induction. It was found that under the conditions of primary generalized seizures induced by picrotoxin, thiosemicarbazide, strychnine, and camphor, digoxin not only shows its own strong anticonvulsant activity but also significantly enhances the anticonvulsant potential of classical AEDs sodium valproate, levetiracetam, and topiramate. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant drug, in particular, the in-depth study of neurochemical mechanisms of its action.

• Klíčová slova
• adjuvant, anticonvulsant, digoxin, levetiracetam, seizures, topiramate, valproate,
• MeSH
• antikonvulziva * terapeutické užití   MeSH
• digoxin * terapeutické užití   MeSH
• kafr terapeutické užití   MeSH
• kardiotonika terapeutické užití   MeSH
• kyselina valproová * terapeutické užití   MeSH
• levetiracetam * terapeutické užití   MeSH
• myši MeSH
• pikrotoxin MeSH
• strychnin MeSH
• topiramat * terapeutické užití   MeSH
• záchvaty * chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva * MeSH
• digoxin * MeSH
• kafr MeSH
• kardiotonika MeSH
• kyselina valproová * MeSH
• levetiracetam * MeSH
• pikrotoxin MeSH
• strychnin MeSH
• topiramat * MeSH

A variety of 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethines and 1,3-dihydro-2H-1,4-benzodiazepin-2-one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin-induced seizure model. The prepared 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7-{(E)-[(4-nitrophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-{(E)-[(4-bromo-2,6-difluorophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 7-[(E)-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.

• Klíčová slova
• 1,3-dihydro-2H-1,4-benzodiazepin-2-ones, anticonvulsant, azomethine, epilepsy, molecular docking,
• MeSH
• antikonvulziva chemická syntéza   chemie   farmakologie   MeSH
• azepiny chemická syntéza   chemie   farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu Rattus MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• pikrotoxin aplikace a dávkování   MeSH
• potkani Wistar MeSH
• Schiffovy báze chemická syntéza   chemie   farmakologie   MeSH
• záchvaty chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• azepiny MeSH
• pikrotoxin MeSH
• Schiffovy báze MeSH

Postictal refractoriness may be taken as an expression of lasting activity of inhibitory systems arresting seizures. We tested drugs interfering with GABAergic inhibitory system in pairs of cortical epileptic afterdischarges induced with 1-min interval in rats. Under control conditions the second stimulation failed to elicit an afterdischarge. This postictal refractoriness was not affected by antagonists of GABAA receptors acting at three binding sites (bicuculline, picrotoxin, benzodiazepine inverse agonist Ro 19-4603) as well as by a less specific antagonist pentetrazol. In contrast, antagonist of GABAB receptors CGP35348 partially blocked the refractoriness. Cooperation of different inhibitory systems is probably necessary to abolish postictal refractoriness in neocortex. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.

• Klíčová slova
• Bicuculline (PubChem CID 102037), CGP35348 (PubChem CID 107699), Cortical seizures, GABA receptors antagonists, Pentylentetrazol (PubChem CID 5917), Picrotoxin (PubChem CID 31304), Postictal refractoriness, Rat, Ro 19-4603 (PubChem CID 127382),
• MeSH
• antagonisté receptorů GABA-A farmakologie   MeSH
• antagonisté receptorů GABA-B farmakologie   MeSH
• azepiny farmakologie   MeSH
• bikukulin farmakologie   MeSH
• elektrická stimulace MeSH
• epilepsie farmakoterapie   patofyziologie   MeSH
• implantované elektrody MeSH
• mozková kůra účinky léků   patofyziologie   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• pentylentetrazol farmakologie   MeSH
• pikrotoxin farmakologie   MeSH
• potkani Wistar MeSH
• receptory GABA-A metabolismus   MeSH
• receptory GABA-B metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antagonisté receptorů GABA-A MeSH
• antagonisté receptorů GABA-B MeSH
• azepiny MeSH
• bikukulin MeSH
• CGP 35348 MeSH Prohlížeč
• organofosforové sloučeniny MeSH
• pentylentetrazol MeSH
• pikrotoxin MeSH
• receptory GABA-A MeSH
• receptory GABA-B MeSH
• Ro 19-4603 MeSH Prohlížeč

Convulsant drugs picrotoxin (0.5 and/or 1 mg/kg, intraperitoneal (i.p.)) and pentylenetetrazol (10 and/or 20 mg/kg, i.p.) were used to compromise GABAergic inhibition, caffeine (75 and/or 150 mg/kg, i.p.) to antagonize adenosinergic system to study the role of inhibition in cortical epileptic afterdischarges. Rats with implanted cortical stimulation and registration electrodes were stimulated four times at 10-min intervals, drugs were injected between the first and second stimulation. Four different phenomena were evaluated: movements directly bound to stimulation were intensified by all three drugs, i.e., excitability of the cerebral cortex was increased. Incidence of two types of afterdischarges (spike-and-wave rhythm and "limbic" type) was not changed by any drug, i.e., the transition of epileptic activity into limbic structures was not increased. Afterdischarges were most efficiently prolonged by caffeine, i.e., caffeine probably interferes with mechanism(s) arresting cortical afterdischarges. The intensity of clonic seizures accompanying spike-and-wave afterdischarges, i.e., spread of epileptic activity into the motor system was only transiently increased by picrotoxin, the effects of caffeine did not reach the level of statistical significance. Our results indicate various mechanisms and diverse role of the two inhibitory systems in generation of evaluated phenomena.

• MeSH
• elektrická stimulace MeSH
• elektroencefalografie MeSH
• epilepsie tonicko-klonická chemicky indukované   patofyziologie   MeSH
• inhibitory fosfodiesteras farmakologie   MeSH
• kofein farmakologie   MeSH
• konvulziva farmakologie   MeSH
• krysa rodu Rattus MeSH
• mozková kůra patofyziologie   MeSH
• pentylentetrazol farmakologie   MeSH
• pikrotoxin farmakologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory fosfodiesteras MeSH
• kofein MeSH
• konvulziva MeSH
• pentylentetrazol MeSH
• pikrotoxin MeSH

The gamma-aminobutyric acid (GABA)-ergic communication between the CNS and the anterior pituitary gland has been documented in numerous histochemical and biochemical studies but electrophysiological studies characterizing the GABAA receptor in the anterior pituitary are still lacking. In the present report we studied the GABA-induced current responses in cultured cells from the anterior pituitary gland of 6- to 10-day-old rats using the patch-clamp technique in the whole cell configuration. Fast application of GABA (100 microM) induced membrane currents in 90% of cells in 2-day-old cultures. The EC50 for GABA was 22.9 microM and the Hill coefficient was 1.8. The responses to GABA (10 microM) were inhibited by bicuculline (2 microM) to 14%, by picrotoxin (5 microM) to 21% and by zinc (10 microM) to 33%. Inhibition to 56% was observed with 6 microM strychnine. The GABA responses were sensitive to diazepam and pentobarbital. Half-maximal potentiation of responses to GABA (10 microM) was found with 1.0 microM diazepam and with 14.4 microM pentobarbital. The maximal potentiation of GABA responses was 222% for diazepam and 195% for pentobarbital. Pentobarbital (100 microM) did not induce any response in anterior pituitary cells in the absence of GABA. The application of GABA at concentrations 10 microM or higher, induced membrane currents that desensitized. Desensitization proceeded as a biexponential process with estimated fast and slow time constants which decreased with concentration. The responses to GABA (300 microM) desensitized to 93% with time constants of 1.4 and 5.3 s. Half-maximal desensitization was found with 13.4 microM GABA.(ABSTRACT TRUNCATED AT 250 WORDS)

• MeSH
• adenohypofýza fyziologie   MeSH
• bikukulin farmakologie   MeSH
• diazepam farmakologie   MeSH
• elektrická vodivost MeSH
• elektrofyziologie MeSH
• GABA antagonisté farmakologie   MeSH
• GABA farmakologie   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• membránové potenciály MeSH
• metoda terčíkového zámku MeSH
• novorozená zvířata MeSH
• pentobarbital farmakologie   MeSH
• pikrotoxin farmakologie   MeSH
• receptory GABA účinky léků   fyziologie   MeSH
• tolerance léku MeSH
• zinek farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• bikukulin MeSH
• diazepam MeSH
• GABA antagonisté MeSH
• GABA MeSH
• pentobarbital MeSH
• pikrotoxin MeSH
• receptory GABA MeSH
• zinek MeSH

The action of ethosuximide (125 or 250 mg/kg, IP) against picrotoxin-induced seizures (3-6 mg/kg, IP) was assessed in rats 12, 18, 25, and 90 days old. In 18-day-old and older controls, picrotoxin regularly elicited clonic seizures; tonic-clonic seizures were induced in all age categories with high consequent mortality. Only the higher dose of ethosuximide (250 mg/kg) increased the latency of clonic seizures in 18- and 25-day-old pups. Tonic-clonic seizures were delayed by ethosuximide in 12-, 18-, and 90-day-old rats. Picrotoxin-induced lethality was suppressed only in 18- and 90-day-old rats by the 250-mg/kg dose of ethosuximide. In contrast, ethosuximide pretreatment increased the incidence of clonic seizures in 12-day-old rats. The results suggest that only high doses of ethosuximide can suppress clonic seizures, and this action is not consistent. Tonic-clonic seizures probably have model-specific sensitivity to ethosuximide because in previous studies ethosuximide completely suppressed pentylenetetrazol-induced tonic-clonic seizures but had no effect on kainic acid-induced tonic-clonic seizures. The suppression of mortality rates is probably due to nonspecific effects of high doses of ethosuximide.

• MeSH
• antikonvulziva farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• epilepsie myoklonické prevence a kontrola   MeSH
• epilepsie tonicko-klonická prevence a kontrola   MeSH
• ethosuximid farmakologie   MeSH
• krysa rodu Rattus MeSH
• pentylentetrazol MeSH
• pikrotoxin antagonisté a inhibitory   toxicita   MeSH
• potkani Wistar MeSH
• záchvaty chemicky indukované   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antikonvulziva MeSH
• ethosuximid MeSH
• pentylentetrazol MeSH
• pikrotoxin MeSH

The convulsant effects of four doses of picrotoxin (PX)-2, 3, 4, and 6 mg/kg s.c.-were evaluated in the first part of the study. The 4-mg/kg dose, which elicited minimal seizures in all animals, generalized tonic-clonic (major) seizures in 75% of rats and fatal outcome in 69% of rats, was chosen for the second part, i.e. for testing the anticonvulsant action of clonazepam (Rivotril Roche, 0.1 or 1 mg/kg i.p.). Clonazepam exhibited a dose-dependent action against PX-induced seizures, being more efficient against major than against minimal seizures.

• MeSH
• antikonvulziva farmakologie   MeSH
• epilepsie chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• injekce intraperitoneální MeSH
• klonazepam farmakologie   MeSH
• krysa rodu Rattus MeSH
• pikrotoxin * MeSH
• potkani Wistar MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• záchvaty chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• klonazepam MeSH
• pikrotoxin * MeSH

The action of MK-801 (NMDA antagonist; 0.1 and 0.5 mg/kg, IP) was tested against picrotoxin-induced seizures (3-6 mg/kg, IP) in rats aged 7, 12, 18, 25, and 90 days. We found MK-801 only inconsistently affected clonic seizures in 12- and 25-day-old rats, whereas tonic-clonic seizures were suppressed or delayed in almost all age groups. In addition, the lethality of picrotoxin was diminished by the higher dose of MK-801 in all age groups. The results suggest: a) different generators for both seizure patterns (clonic and tonic-clonic), b) an involvement of NMDA receptors in the genesis of tonic-clonic seizure pattern, and c) an interaction of MK-801 with GABAergic transmission throughout the entire development studied.

• MeSH
• ataxie chemicky indukované   patofyziologie   MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát farmakologie   MeSH
• epilepsie tonicko-klonická chemicky indukované   prevence a kontrola   MeSH
• krysa rodu Rattus MeSH
• pikrotoxin * antagonisté a inhibitory   toxicita   MeSH
• potkani Wistar MeSH
• stárnutí fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dizocilpinmaleát MeSH
• pikrotoxin * MeSH

• MeSH
• bikukulin antagonisté a inhibitory   MeSH
• fenobarbital farmakologie   MeSH
• inbrední kmeny potkanů MeSH
• krysa rodu Rattus MeSH
• pentylentetrazol MeSH
• pikrotoxin antagonisté a inhibitory   MeSH
• záchvaty chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• bikukulin MeSH
• fenobarbital MeSH
• pentylentetrazol MeSH
• pikrotoxin MeSH