Maximal Electroshock-induced Seizures Research Articles

Anticonvulsant and antioxidative activity of hydroalcoholic extract of tuber of Orchis mascula in pentylenetetrazole and maximal electroshock induced seizures in rats

Ethnopharmacological relevanceOrchis mascula tuber is used in many polyherbal formulations as a nerve tonic in India. Aim of the studyIn the present study, effect of hydroalcholic extract of O. mascula (HEOM) tuber was evaluated against seizures, seizure-induced oxidative stress and cognitive deficit in pentylenetetrazole and maximal electroshock-induced seizures in rats. Materials and methodsHEOM was administered orally 30min before induction of seizures by pentylenetetrazole (PTZ; 60mg/kg, i.p) or maximal electroshock (MES; 70mA). Elevated plus maze and passive avoidance tests were used to assess the learning and memory. Oxidative stress was studied by estimation of reduced glutathione and lipid peroxidation. Whole brain total cholinesterase activity was also evaluated. ResultsHEOM produced 33.3%, 50% and 66.7% protection in PTZ model and 16.7%, 16.7% and 33.3% at 250, 500 and 1000mg/kg, respectively, in MES-induced seizures. Pre-treatment with HEOM significantly decreased the retention transfer latency in elevated plus maze test, and an increase in the retention latency in passive avoidance test was observed. Oxidative stress induced by seizures was also attenuated as indicated by significant increase in GSH and decrease in MDA levels in HEOM treated groups. PTZ and MES caused a significant decrease in AChE and BChE activities, which was prevented by HEOM. ConclusionsHEOM thus showed protection against seizures, prevented the associated memory impairment probably by modulating cholinergic status and reducing oxidative stress.

Synthesis, Characterization, and Biological–Pharmacological Evaluation of New Phosphazenes Bearing Dioxybiphenyl and Schiff Base Groups

A new spirocyclophosphazene, 2,2-bis(2-formylphenoxy)-4,4,6,6-bis[spiro(2',2″-dioxy-1'-1″-biphenylyl)]cyclotriphosphazene (3), was obtained from the reaction of 2,2-dichloro-4,4,6,6-bis[spiro(2',2″-dioxy-1'-1″-biphenylyl)]cyclotriphosphazene (2) with 2-hydroxybenzaldehyde. New phosphazene derivatives bearing Schiff base and dioxybiphenyl groups have been synthesized by the reactions of 3 with different amines. The structures of the compounds were defined by elemental analysis, IR, (1) H, (13) C, and (31) P NMR spectroscopy. All the synthesized compounds were screened for their antibacterial activity against both types of Gram-negative and Gram-positive bacteria. The most potent antibacterial compound of this series was compound 12 which has the low MIC value of 3.75-0.9375 µg/mL. Both minimal inhibitory concentrations (MIC) and inhibition zones were determined in order to monitor the efficacy of the synthesized compounds. New compounds were also screened for anticonvulsant, CNS depressant, and sedative-hypnotic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight phosphazenes were examined in the maximal electroshock-induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. Compounds 4, 5, and 11 were found to be active in both MES screen and scPTZ screen at 0.5 h. All except 12 showed more than 44% decrease in locomotor activity after 1 h of compound administration via actophotometer screen. CNS-depressant activity screened with the help of the forced swim method resulted in some potent compounds. Except for 7 and 12 other tested compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time.

Effect of hydrochlorothiazide on the anticonvulsant action of antiepileptic drugs against maximal electroshock-induced seizures in mice

BackgroundThe purpose of this study was to evaluate the effect of hydrochlorothiazide (HCTZ), a thiazide-type diuretic and an antihypertensive drug, on the anticonvulsant activity of numerous antiepileptic drugs (AEDs: carbamazepine – CBZ, phenytoin – PHT, valproate – VPA, phenobarbital – PB, oxcarbazepine – OXC, lamotrigine – LTG and topiramate – TPM). MethodsThe effects of HCTZ and AEDs on convulsions were examined in the maximal electroshock seizure (MES) test in mice. Additionally, adverse effects of combined treatment with HCTZ and the AEDs in the passive avoidance task and chimney test were assessed. All drugs were injected intraperitoneally (ip) at single doses. ResultsThe data obtained indicate that HCTZ (100mg ip) enhanced the anticonvulsant action of CBZ, decreasing its ED50 value from 11.9to 7.7mg/kg (p<0.05), and had no impact on the antielectroshock activity of the other AEDs. The observed interaction between HCTZ and CBZ was not pharmacokinetic in nature as HCTZ did not alter free plasma (non-protein-bound) and total brain concentrations of CBZ. The combined treatment with HCTZ and the AEDs was free from side-effects on motor performance and long-term memory in mice. ConclusionsTo the degree, the experimental data can be transferred to clinical conditions, the use of a single dose of HCTZ in patients receiving VPA, PHT, PB, OXC, LTG or TPM, seems neutral regarding their anticonvulsant potency. Acute HCTZ may positively influence the anticonvulsant action of CBZ in epileptic patients.

UPLC–TOF-MS analysis of Galium spurium towards its neuroprotective and anticonvulsant activities

Ethnopharmacological relevanceGalium species have been reported to be used against epilepsy in traditional Turkish folk medicine. Aim of studyThe present work was undertaken to evaluate the in vivo anticonvulsant and in vitro neuroprotective effects of Galium spurium L. and to determine the major constituents by UPLC–TOF-MS. Materials and methodsAnticonvulsant activity of the aerial parts of Galium spurium was investigated using pentylenetetrazole, picrotoxin, and maximal electroshock-induced seizure animal models. In order to evaluate the safety, neurotoxicity (Rota rod test) of the ethanol extract was also determined. In vitro neuroprotective effect of the ethanol extract of Galium spurium was assessed by acetylcholinesterase and butrylcholinesterase inhibitions. Ultra Performance Liquid Chromatography–Time of Flight Mass Spectrometer (UPLC–TOF-MS) was used to identify the major compounds in the extract. ResultsIn pentylenetetrazole-induced seizure, the ethanol extract at doses of 250 and 1000mg/kg prolonged the onset of seizures. Similarly, Galium spurium (250 and 500mg/kg) significantly delayed the onset of picrotoxin-induced seizures in mice and these doses also exhibited 12.5% and 17% protection, respectively, against picrotoxin-induced seizures. Furthermore, Galium spurium extract showed a significant protective effect against maximal electroshock-induced seizures at doses of 250 and 1000mg/kg (50% and 37.5%, respectively) and also all tested doses prolonged the onset of seizures. No motor co-ordination was observed with intraperitoneal injection of Galium spurium extract at doses of 500 and 1000mg/kg. The extract exhibited 16.2% inhibition against butrylcholinesterase at 200μg/mL concentration, whereas it did not inhibit acetylcholinesterase. Phytochemical analysis of the extract based on the MS data by UPLC–TOF-MS, ten major compounds (phenolic and triterpenic acids, flavonoids and iridoids) were determined. ConclusionsThe results indicate that Galium spurium may have anticonvulsant activity against picrotoxin and maximal electroshock-induced seizures in mice. Phenolic acids, flavonoids and iridoids might be responsible for anticonvulsant activity. The results offer possible beneficial effects by the plant's aerial parts and may suggest a realistic explanation for its traditonal usage in epilepsy.

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.

Effect of artesunate on maximal electroshock and pentylenetetrazole-induced seizures in albino mice

Artemisinin-based combination therapies are highly efficacious, and they are now listed as first-line therapies for uncomplicated malaria in most countries where malaria is endemic. Neurotoxicity of artemisinins is a growing concern. However, no studies have reported its antiepileptic or epileptogenesis potential, hence the present study was undertaken to explore the activity of artesunate in experimentally induced seizures in rodent models. Artesunate at doses 36.4 and 72.8 mg/kg respectively significantly reduced the duration of the hind limb extensions (3.033±1.493 and 2.033±1.383, respectively) when compared to the control (P<0.0001) in the maximal electroshock-induced seizure model. However, no significant decrease was noted in the duration of clonic convulsions in a pentylenetetrazole-induced seizure model indicating lack of activity in petit mal epilepsy. The results of the present study indicate that artesunate at both the doses employed showed a significant anticonvulsant activity in the maximum electroshock-induced seizure model suggesting its potential utility in the management of generalized tonic-clonic seizures and partial seizures. Further studies regarding its mechanism of action are warranted. Key words: Anticonvulsant, artesunate, neurotoxicity, pentylene tetrazole-induced seizures and maximum electroshockinduced seizures

Design, anticonvulsive and neurotoxic properties of retrobenzamides. N-(Nitrophenyl)benzamides and N-(aminophenyl)benzamides.

Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values--including the dose offering anticonvulsant protection in 50% of tested animals (ED50) and protective indices--obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.

The interactions of atorvastatin and fluvastatin with carbamazepine, phenytoin and valproate in the mouse maximal electroshock seizure model

The aim of this study was to determine the influence of acute (single) and chronic (once daily for 7 consecutive days) treatments with atorvastatin and fluvastatin on the anticonvulsant potential of three antiepileptic drugs: carbamazepine, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of both statins on the adverse effect potential of three antiepileptic drugs were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). To evaluate the pharmacokinetic characteristics of interaction between antiepileptic drugs and statins, the total brain concentrations of antiepileptic drugs were estimated with the fluorescence polarization immunoassay technique. Results indicate that atorvastatin at doses up to 80mg/kg in chronic experiment attenuated the anticonvulsant potential of carbamazepine by increasing its ED50 value against maximal electroconvulsions. Acute fluvastatin (80mg/kg) enhanced the anticonvulsant potential of carbamazepine and valproate by decreasing their ED50 values. Acute fluvastatin (80mg/kg) also markedly increased the total brain carbamazepine concentration by 61% in a pharmacokinetic reaction. Atorvastatin (acute and chronic) and fluvastatin (chronic) in combinations with valproate impaired long-term memory in mice. Both statins in combinations with all three antiepileptic drugs had no impact on their adverse effects in the chimney test. Based on this preclinical study, one can conclude that chronic administration of atorvastatin reduces the anticonvulsant action of carbamazepine and acute fluvastatin can enhance the anticonvulsant potency of the carbamazepine and valproate. The former interaction was pharmacokinetic in nature.

The α-asarone/clofibrate hybrid compound, 2-methoxy-4-(2-propenyl)phenoxyacetic acid (MPPA), is endowed with neuroprotective and anticonvulsant potentialities

2-methoxy-4-(2-propenyl)phenoxy acetic acid (MPPA) is a synthetic drug previously developed to mimic hypolipidemic activity and reduce side-effects of α-asarone, a vegetal extract used in traditional medicine to treat cardiovascular, neurological and other human disorders. MPPA was here evaluated in a battery of tests previously used to characterize anticonvulsant/neuroprotective and toxic potential of α-asarone in mice. MPPA toxicity was limited and doses up to 100 mg/kg induced neither hypothermia, nor reduction of spontaneous locomotor activity nor failure in rotarod test. Dose-dependent potentiation of the pentobarbital-induced sleeping was, however, observed at doses higher than 12.5 mg/kg. Little or no protection was provided by MPPA against seizures induced by N-methyl-D-aspartate. Moderate protection against subcutaneous pentylenetetrazol- and picrotoxin-induced seizures in mice, along with potentiation of pentobarbital-induced sleep, suggested GABAergic mechanisms. In maximal electroshock-induced seizures, MPPA protected 20% tested mice at 30 mg/kg and shortened recovery phase in convulsing mice, suggesting some action on neuronal voltage-gated sodium channels. High efficacy of MPPA was further observed in magnesium-dependent audiogenic seizures test, a murine model responsive to a variety of anticonvulsant, neuroprotective and antioxidant compounds. In this test, 50% animals were protected by 10 mg/kg MPPA, highlighting strong brain protective potential. In vitro, MPPA exhibited a superoxide-scavenging capacity about two-fold higher than that of α-asarone. Taken as a whole, present data support that MPPA is less toxic and more brain protective than α-asarone, and represents a worthy emerging neuroprotective/anticonvulsant compound endowed with a large activity spectrum including antioxidant, neuroprotective-like, moderate pro-GABAergic and sodium blockade mechanisms.

Anti-nociceptive, anxiolytic and anticonvulsant effects of an aqueous leaf extract of Leea guineensis G. Don (Family: Leeaceae)

Leea guineensis G. Don (Family: Leeaceae) is an evergreen shrub or small tree used in Ghanaian traditional medicine to treat various ailments including epileptic fits and pain. However, little scientific evidence exists to support its use. The present study examined the anti-nociceptive, anti-anxiety and anticonvulsant effects of the aqueous leaf extract of L. guineensis (LGE) in murine models of pain (formalin test), anxiety (elevated plus-maze and light/dark box tests) and convulsion (pentylenetetrazole-, picrotoxin- and maximal electroshock-induced seizures tests). LGE (30 to 300 mg/kg,p.o.) and the positive control morphine (3 to 10 mg/kg, i.p.) exerted profound dose-dependent anti-nociceptive activity in both phases of the formalin test. LGE (30 to 300 mg/kg, p.o.) also showed anxiolytic effects similar to diazepam (0.1 to 1.0 mg/kg, i.p.) but contrary to pentylenetetrazole (3 to 30 mg/kg, i.p.). LGE increased the frequency and duration of open arm exploration while decreasing the protected forms of stretch-attend postures and head-dips in the elevated plus-maze. It also decreased the emergence latency of mice into the lit compartment of the light/dark box and increased the amount of time spent there. LGE (30 to 300 mg/kg, p.o) also exhibited significant anticonvulsant activity by protecting mice against pentylenetetrazole-, picrotoxin- and maximal electroshock-induced seizures. At all the doses used, LGE produced no motor deficits in mice. Together, the results suggest that the extract has anti-nociceptive, anxiolytic and anticonvulsant properties which support its traditional use. Key words: Leea guineensis, seizures, maximal electroshock, formalin test, elevated plus-maze, light/dark box.

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.

Synthesis, characterization and pharmacological evaluation of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives as potent anticonvulsant agents

A series of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives were synthesized by coupling it with different substituted aldehydes, acetophenone, and benzophenones in presence of absolute ethanol along with catalytic amount of glacial acetic acid. All the synthesized compound 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 using various seizures models like maximal electroshock-induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) at a dose of 30, 100, and 300 mg/kg body weight and anticonvulsant activity was noted at 0.5 h and 4 h time intervals after the drug administration. Compound 1a (E)-N′-2-benzylidene isonicotinohydrazide, 1g (E)-N′-2-ethoxybenzylidene isonicotinohydrazide, 1k (E)-N′-3-flourobenzylidene isonicotinohydrazide and 3a (E)-N′-diphenylmethylene isonicotinohydrazide showed protection in MES model, which indicates that these compounds have the ability to prevent the spread of seizure at 300 mg/kg dose and showed protection at 0.5 h duration. Compound 3a was also found to be active in scPTZ screen at a dose of 300 mg/kg. In neurotoxicity screen, all the synthesized compounds were found non-toxic except compounds 1n, 2a, and 3b. Further compounds 1a, 1g, 1k, and 3a were also evaluated in the minimal clonic seizure model and exhibited potent anticonvulsant activity with lower neurotoxicity. Among all synthesized derivatives, analogue 3a was found to exhibit protection in MES and scPTZ seizure models. This study proved that isonicotinoyl hydrazides synthesized by condensing isoniazid with various aldehydes and ketones displayed moderate to potent anticonvulsant activity.

Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and valproate) in the mouse maximal electroshock seizure (MES) model. The results indicate that WIN (10mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test in mice. WIN (5mg/kg) potentiated the anticonvulsant action of carbamazepine and valproate, but not that of phenytoin or phenobarbital in the MES test in mice. However, WIN administered alone and in combination with carbamazepine, phenytoin, phenobarbital and valproate significantly reduced muscular strength in mice in the grip-strength test. In the passive avoidance task, WIN in combination with phenobarbital, phenytoin and valproate significantly impaired long-term memory in mice. In the chimney test, only the combinations of WIN with phenobarbital and valproate significantly impaired motor coordination in mice. In conclusion, WIN enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test. However, the utmost caution is advised when combining WIN with classical antiepileptic drugs due to impairment of motor coordination and long-term memory and/or reduction of skeletal muscular strength that might appear during combined treatment.

Anticonvulsant and muscle relaxant activity of the ethanolic extract of stems of Dendrophthoe falcata (Linn. F.) in mice

Objective:To investigate the anticonvulsant and muscle relxant activity of ethanolic extract of stems of Dendrophthoe falcata in mice.Materials and Methods:The ethanolic extract of stems of D. falcata (100, 300 and 500 mg/kg, p.o.) was studied for its anticonvulsant effect on maximal electroshock-induced seizures and muscle relaxant activity at the same dose level using rota rod and traction test in mice.Results:Preliminary phytochemical analysis revealed presence of proteins, carbohydrates, glycosides, steroids, triterpenes, flavonoids, tannins and phenolic compounds. D. falcata ethanolic extract (DFEE) (100, 300 and 500 mg/kg, p.o.) significantly (P<0.001) inhibited seizures induced by MES, reduced the duration of Hind limb tonic extensor phase (HLTE) and a decline in motor coordination.Conclusion:The ethanolic extract possesses anticonvulsant activity and muscle relaxant activity.

Sedative and antiepileptic effects of Anthocephalus cadamba Roxb. in mice and rats

Objective:The aim of the present study was to evaluate the sedative and antiepileptic activities of ethanolic extract of Anthocephalus cadamba (ACE) bark in various experimental animal models.Materials and Methods:ACE was tested at three doses viz. 100, 200 and 400 mg/kg p.o. We used ketamine-induced sleeping time model to test the sedative property of the extract where, onset and duration of sleep were observed. A paradigm of anticonvulsant models (pentylenetetrazole, isoniazid and maximal electroshock-induced seizures) were used to evaluate its protective effect against absence and generalized types of seizures. Onset of clonic convulsions, tonic extension and time of death were observed in PTZ and INH-induced seizure models. In MES model, duration of tonic hind leg extension and onset of stupor were observed.Results:ACE showed significant increase in ketamine induced sleeping time. It also exhibited significant increase (P<0.05, 0.01 and 0.001) in latency to clonic convulsion, tonic extension and time of death in PTZ and INH models at all tested doses, whereas in the MES model, the lower dose was found to be effective when compared with the higher doses (200 and 400 mg/kg, p.o.).Conclusion:The results of the present investigation demonstrated that ACE possesses sedative and antiepileptic activities.

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.

Synthesis, anticonvulsant and neurotoxic activity of some new 2,5-disubstituted-1,3,4-oxadiazoles

Two novel series 2a–2d (2Z)-N-[5-(4-substituted)phenyl-1,3,4-oxadiazol-2-yl]-2-[(2Z)-3,7-dimethylocta-2,6-dien-1-ylidene]hydrazinecarboxamide and 1a–1d 5-(4-substituted)phenyl-N-[(1Z,2Z)-3,7-dimethylocta-2,6-dien-1-ylidene]-1,3,4-oxadiazol-2-amine have been synthesized and screened for their anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100 and 300 mg/kg body weight 2,5-disubstituted-1,3,4-oxadiazole analogues were examined in the maximal electroshock induced seizures (MES) and subcutaneous metrazole (ScMET) induced seizure models in mice. Amongst all the compounds, 1a–1d and 2a–2d, one compound 1a exhibited activity at 100 mg/kg body weight at 0.5 and 4 h in ScMET, respectively. Compound 2b showed anticonvulsant activity at 100 mg/kg without activity in ScMET and neurotoxicity. The neurotoxicity was assessed by rotorod method, and all compounds (except 1a) were found to be safe at maximum administered dose.

Design and synthesis of some novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-phenylquinazoline-4(3H)-ones as possible anticonvulsant agent

A novel series 7(a–f) 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2 phenylquinazoline-4(3H)-ones have been synthesized and screened for its anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-disubstituted-quinazolin-4(3H)-ones were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data were consistent with the structure of newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. In the prepared series, 7a was found to be active in the MES screen at 0.5 h, whereas 7f showed anticonvulsant activity at both 0.5 and 4 h.

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.

Low dose of bupropion significantly enhances the anticonvulsant activity of felbamate, lamotrigine and topiramate in mice

Experimental evidence indicates that bupropion hydrochloride, an antidepressant and a first-line smoking cessation aid, exerts dose-dependently anticonvulsant and convulsant effects. In this study, chronic bupropion pretreatment intraperitoneally (i.p.) for 14 days in a dose of 5 mg/kg reduced the ED 50 (i.e. the dose protecting 50% of mice against electroconvulsions) of lamotrigine, topiramate, and felbamate from 4.58, 60.95, and 48.79 (antiepileptic + vehicle) to 3.01, 41.68, and 37.28 mg/kg (antiepileptic + bupropion), respectively, against maximal electroshock-induced seizures in mice. Bupropion significantly increased the plasma and brain concentrations of lamotrigine. Plasma concentration of topiramate was elevated, however, the brain concentration of the drug was not affected. Neither plasma nor brain concentrations of felbamate were elevated by bupropion administration. Bupropion did not exacerbate motor coordination impairment caused by the antiepileptic drugs in the rotarod test. Chronic administration of bupropion significantly potentiates the protective activity of lamotrigine, topiramate, and felbamate against maximal electroshock-induced seizures. A pharmacokinetic interaction is responsible for the effect of bupropion co-administered with lamotrigine.