Anticonvulsant property of celecoxib in maximal electroshock seizure: Correlating the role of inflammation in pathophysiology of epileptic seizures

Background: Epilepsy is an abnormal excessive electric neuronal activity and always represents by recurrent seizures. There is positive feedback cycle between epileptogenesis and brain inflammation. It has been proved that an inflammatory enzyme, cyclooxygenase (COX) (especially isoform-2, a constitutive enzyme), expressed in some important parts of the central nervous system and is responsible to induced inflammation locally and having seizurogenic property. Aim and Objective: The goal of this study was to see if celecoxib (a selective COX-2 inhibitor) could reduce the maximal electroshock seizure (MES)-induced seizures in mice. Materials and Methods: Celecoxib injected intraperitoneally in two different doses 5 mg/kgb/w and 10 mg/kg b/w, in albino Swiss mice and in two different phases. MES was elicited and length of different phases was noted. Length of tonic hindlimb extension was considered as indicator of anti-epileptic activity. Results: Celecoxib, when given intraperitoneally, exert significant reduction in the duration of THLE. This action of celecoxib strongly suggests the involvement of inflammation in the pathophysiology of epilepsy. Conclusion: The findings are suggestive of the therapeutic significance of celecoxib, as a future antiepileptic agent for seizure management.

Effect of ethanolic extract of Centella asiatica on maximal electroshock seizure in albino mice

Background: Animal models had always served as integral part in introducing newer drugs for epilepsy. India has long tradition of using herbal medicines. Centella asiatica is an ingredient of various ayurvedic preparations to treat brain related disorders like insanity, memory loss and epilepsy. This research is done to find out the usefulness of Centella asiatica in epilepsy.  Methods: Ethanolic extract of the plant is prepared using Soxhlet apparatus. Experimental seizure is induced in albino mice by maximal electroshock method. Resulting seizure goes through different phases. Duration of the phase of hind limb extension was the measured data. Clinically used anti epileptic drugs can abolish hind limb extension. Effect is compared to that of standard drug phenytoin. Four different doses of the plant extract; 100mg, 200mg, 500mg and 1000mg per kilogram bodyweight was given orally. Statistical analysis of data was done by one way ANOVA and Dunnett test.Results: Ethanolic extract of Centella asiatica exhibited statistically significant protection from maximal electroshock seizures. All given doses of the extract had p<0.05 when compared to control.Conclusions: Centella asiatica is potential source of anti-epileptic drug. Detailed phytochemical studies and animal experiments are recommended.

Design and Synthesis of New Derivatives of (E)-3-(5-((phenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one for their Anticonvulsant Potential

Objective: The objective of the paper was to design and synthesize new derivatives of ((E)-3-(5-((substitutedphenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one and evaluated for their anticonvulsant potential. Materials and Methods: Various synthesis of (E)-3-(5-(substitutedaminomethyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one derivatives has been synthesized by reacting 2-substituted benzoxazin-4-one with (E)-2-(4-Substituedstyryl)-4H-benzo[d] [1,3]oxazin-4-one. All synthesized compounds have been characterized by the infrared, 1HNMR, and mass spectral analysis. Proposed compounds have been evaluated for anticonvulsant potential by subcutaneous pentylenetetrazole and maximal electroshock seizure model and compared with the reference drug phenytoin and carbamazepine. Neurotoxicity study of the synthesized compounds was also performed. Results and Discussion: The anticonvulsant evaluation of synthesized compound QNM-1, QNM-2, QNM-4, QNM-6, QNM-9, QNM-11, QNM-13, and QNM-15 has shown seizure protection at 100 mg/kg dose after 30 min and 4 h, so they have good onset of action as quickly reach brain and have prolonged action reveal that compound metabolized slowly. Whereas compound QNM-7, QNM-8, and QNM-12 were moderate active and reveal that their high concentration is required to cross blood brain barrier. Compounds QNM-3, QNM-5, QNM-10, and QNM-14 were less active. Compounds having chlorine, bromine, fluorine, and nitro in the phenyl moiety have shown good activity when attached to para group but the addition of meta and ortho group of the same may provide least active compounds and in last fluorine compounds have shown comparative less active compounds. Conclusion:The Pharmacological evaluation suggest that eight synthesized compounds have shown promising anticonvulsant potential and bulkier compounds can easily penetrate BBB to exert their effect.

Anticonvulsant activity of nicardipine in experimentally induced seizures in wistar albino rats.

Background: The objective of the study was to evaluate the anticonvulsant activity of nicardipine in wistar albino rats.Methods: Anticonvulsant activity of nicardipine in a dose 10 mg/kg, and its effect with the standard drug lamotrigine (5 mg/kg) was studied in a maximal electroshock seizures (MES) experimental animal model.Results: Nicardipine in dose of 10 mg/kg showed significant anticonvulsant effect (p<0.001) and combination with standard drug lamotrigine (p<0.001) also showed more significant anticonvulsant effect in MES model.Conclusions: Nicardipine is having anticonvulsant activity and it also potentiates the anticonvulsant effect of lamotrigine in MES model.

Assessment of efficacy of promethazine on seizure activity and its interactions with antiepileptic drugs lorazepam and sodium valproate in rats

Background: Presently available antiepileptic drugs are effective in controlling seizures in more than half of patients of all epilepsy but use is often limited by adverse effects. H1 receptor antagonists, have a controversial status in patients of epilepsy. Both pro and antiepileptic effect has been documented in various animal studies. Hence, this study was designed to see the effect of promethazine, an H1 antihistaminic drug and its interactions with antiepileptic drugs lorazepam and sodium valproate in rats.Methods: The effect of promethazine (10 mg/kg) and its interactions with antiepileptic drugs lorazepam and sodium valproate was assessed by using maximal electroshock seizures (MES) and chemoshock pentylenetetrazol (PTZ) method.Results: Promethazine along with lorazepam and sodium valproate in subtherapeutic doses exerted significant protection against MES induced seizures whereas no such protection was observed with PTZ method rather the seizure threshold was reduced.Conclusions: Subtherapeutic doses of promethazine alone and in combination with lorazepam and sodium valproate showed protection against seizures in MES method. However, proconvulsant effect was seen with PTZ method. This shows dual behavior of promethazine on MES and PTZ induced seizures.

Study of anticonvulsant activity of acetazolamide on albino rats and its influence on anticonvulsant activity of sodium valproate

Background: Epilepsy is a common neurological disorder. 30-40% of patients will continue to have seizures despite the use of antiepileptic drugs either alone or in combination. The present study is undertaken to evaluate the anticonvulsant activity of Acetazolamide (ACZ) in albino rats and its influence on anticonvulsant activity of sodium valproate.Methods: Albino rats (150-200gms) of male sex were randomly selected, from central animal facility, MMCRI, Mysore. They were divided into 6groups (per model) of 6 rats each, control group-normal saline 0.5ml, standard group-sodium valproate (300mg/kg), dose 1-ACZ (8.75mg/kg), dose 2-ACZ (17.5mg/kg) and dose 3-ACZ (35mg/kg), dose 4-ACZ (8.75mg/kg) with sodium valproate (150mg/kg). The anti-convulsant activity was screened using MES model and PTZ model.Results: Results were analysed by ANOVA followed by post hoc Fisher’s LSD test. The ACZ has shown anticonvulsant activity at the dose of 17.5mg/kg and 35mg/kg body weight and combination of ACZ 8.75mg/kg with sodium valproate 150mg/kg both in MES model and PTZ model. The anticonvulsant activity of ACZ was less when compared to Sodium Valproate in both MES model and PTZ model. The anticonvulsant activity of combination, ACZ 8.75mg/kg with Sodium valproate 150mg/kg was comparable and more significant when compared to standard drug alone in MES model and PTZ model.Conclusions: The ACZ has shown anticonvulsant activity in MES model and PTZ induced seizure model of epilepsy. This study has shown that ACZ potentiated the effect of sodium valproate and can be used as add on drug with sodium valproate in epilepsy.

Fluoxetine enhances maximal electroshock seizure threshold in Albino rat model when compared to phenytoin

Background: Individuals with epilepsy have a higher incidence of psychiatric disorders than person without epilepsy. Epidemiological studies have shown that the co-morbidity of epilepsy and depression to be high as 50%. The conventional anti-depressants are believed to lower the seizure threshold making it difficult to treat the co-morbid depression, but animal studies have shown SSRIs, a common anti-depressant, to have anti-convulsant properties. So, we propose to study the anticonvulsant effects of fluoxetine, a SSRI, in albino rats against maximal electroshock seizure and to compare against a standard antiepileptic drug phenytoin.Methods: The anticonvulsant effect of fluoxetine was observed in model of maximal electroconvulsive seizure threshold in albino rats. The animals were divided into 3 groups having 6 animals each, receiving distilled water, fluoxetine and phenytoin respectively. The drugs were given orally, and the effect was observed on day 7, 14 and 21. Tonic hind-limb extension was taken as the parameter of electroshock seizure. The effects were compared against a standard anti-seizure drug phenytoin.Results: Fluoxetine showed significant elevation of the seizure threshold following 14 days of administration (P value 0.031). The effect was comparable to phenytoin with no significant difference after 7, 14 and 21 days of treatment (P-value 0.485, 0.699 and 0.818 respectively) though phenytoin showed significant anti-seizure effect since day 7 of treatment.Conclusions: Fluoxetine showed significant anti-seizure activity against electroconvulsive seizure in albino rats.

Anticonvulsant activity of nitrendipine in albino mice.

Background: The objective is to evaluate the anticonvulsant activity of nitrendipine in seizure-induced mice. Methods: Albino mice (25-30 g) of either sex were randomly selected and divided into four groups of six mice each. After overnight fasting, Group I received 0.25 ml of propylene glycol and served as the control, Group II received valproic acid (110 mg/kg orally) as standard, Groups III received 5 mg/kg of nitrendipine and 100 mg/kg of valproic acid, Group IV received 5 mg/kg of nitrendipine and 75 mg/kg of valproic acid, and Group V received 5 mg/kg of nitrendipine and 50 mg/kg of valproic acid all of which were administered orally 60 mins prior to the test in this acute study. The anticonvulsant activity was screened using maximal electroshock (MES) model and pentylenetetrazole (PTZ) model. Results: The nitrendipine showed a considerable reduction in the duration of hindlimb extensor phase in MES model and also delayed the latency of seizures induced by PTZ when compared with control group. The probable mechanism of anticonvulsant action of nitrendipine could be due to its interference with the gamma amino butyric acid type aminergic mechanism, modulation of nicotinic, and N-methyl-D-aspartate receptors. Conclusion: Nitrendipine possesses the anticonvulsant activity and has a beneficial role in epilepsy.

Pro-Convulsant Effect of Olanzapine, an Atypical Antipsychotic on Maximal Electro Shock Induced Seizures in Wistar Albino Rats.

Objectives: The aim of the study was to investigate the chronic effect of Olanzapine; an atypical antipsychotic drug on maximal electroshock (MES) induced seizures in Wistar albino rats. Methods: Olanzapine (2mg/kg, 10 days orally) was used to study its effect on MES induced seizures in Wistar albino rats. Duration of the tonic hind limb extension was noted. Results: Olanzapine (2mg/kg) significantly (p<0.001) increased the duration of hind limb extension induced by MES. Conclusions: The data suggests that Olanzapine, the atypical antipsychotic drug has a proconvulsant action.

Anticonvulsant Activity of Moringa Oleifera in Swiss Albino Mice.

Objectives: The aim of the study was to investigate anticonvulsant effect of Moringa oleifera on maximal electroshock (MES), pentylenetetrazole (PTZ) and pilocarpine induced seizures. Methods: The ethanolic extract of Moringa oleifera leaves (200mg/ Kg) was used to study its anticonvulsant effect on MES, PTZ and pilocarpine induced seizures in Swiss albino mice. Suppression of the tonic hind limb extension, duration of convulsion, abolition of convulsions was noted respectively for the above tests. Results: The ethanolic extracts of Moringa oleifera leaves (200mg/ Kg) significantly (p<0.001) abolished the hind limb extension induced by MES. The same dose also significantly (p<0.001) protected the animals from PTZ induced tonic convulsions. None of the animals treated with same dose of plant extract reached the status epilepticus state in pilocarpine induced seizures. Conclusions: The data suggests that the ethanolic extracts Moringa oleifera leaves may produce its anticonvulsant effect via different mechanisms since it prevented the hind limb extension induced by MES, decreased the duration of convulsions produced by PTZ and abolished status epilepticus in pilocarpine induced seizures.

Study of potential drug-drug interactions between benzodiazepines and four commonly used antiepileptic drugs in mice.

Background: Benzodiazepines (BZD) is one of the commonly used drug groups for certain neurological diseases. As sometimes, the anti-epileptic drugs (AEDs) may be used concomitantly with BZD there is a potential for drug-drug interactions. Study aimed to study potential drug-drug interactions between four commonly used AEDs (phenytoin, carbamazepine (CBZ), phenobarbitone, sodium valproate) and BZD (diazepam, clonazepam) in mice using maximal electroshock seizure (MES) method and pentylenetetrazole (PTZ) method. Methods: Adult male albino mice were divided into four different groups of six animals each and anti-epileptic activity was assessed using MES method and PTZ method. Group I acted as a control, Group II received any one of the four AEDs (phenytoin, CBZ, phenobarbitone or sodium valproate) in sub-effective doses, Group III received diazepam or clonazepam alone, Group IV received a combination of diazepam or clonazepam with any one of the AEDs. Results: In MES method, the groups receiving combination of diazepam with phenytoin and CBZ showed significant protection compared to the control group (p<0.01 and p<0.02), respectively. However, diazepam in combination with sodium valproate and phenobarbitone did not show any significant protection compared to the control group and individual antiepileptic group. All the four antiepileptic showed significant protection against MES seizure in combination with clonazepam when compared to control group. In PTZ method, combination of sodium valproate with clonazepam showed significant protection compared to control group (p<0.02). However, this was not observed with diazepam-valproate combination. Conclusion: Clonazepam potentiates the action of all the four anti-epileptics while diazepam potentiates only phenytoin and CBZ against MES seizures. Clonazepam but not diazepam potentiates the action of sodium valproate against PTZ seizures.

Antiepileptic potential of Anisomeles indica (Linn.) Kuntze aerial parts in pentylenetetrazole-induced experimental convulsions in Wistar rats.

The chloroform (4.20% w/w), ethyl acetate (4.23% w/w) and aqueous decoction (12.11% w/w) extracts of the aerial parts of A. indica were screened for the antiepileptic activity against maximal electroshock (MES) model and pentylenetetrazole (PTZ) models at  doses of 200, 400 mg/kg, po once. Phenytoin and diazepam (25 and 2 mg/kg, ip) were used as standard drugs in MES and PTZ model, respectively. Further, ethyl acetate extract (active extract) was fractionated into flavonoid and tannin fraction, which were subsequently evaluated for the antiepileptic potential against both MES and PTZ models at a dose of 50 mg/kg, po. Pretreatment with ethyl acetate extract 200, 400 mg/kg, po, for 1 week showed significant antiepileptic activity against PTZ induced convulsions only. Isolated flavonoid fraction showed more potent antiepileptic activity as compared to ethyl acetate extract, without any neurotoxic effect. However, tannin fraction did not produce antiepileptic activity against PTZ induced convulsions. It may be concluded that the flavonoids fraction of ethyl acetate extract of aerial parts of A. indica, but not the aqueous decoction has antiepileptic potential, without producing neurotoxic effects.

Anticonvulsant and antioxidant activity of aqueous leaves extract of Desmodium triflorum in mice against pentylenetetrazole and maximal electroshock induced convulsion

The present investigation was aimed to study an anticonvulsant activity of aqueous extract of Desmodium triflorum (L.) DC., Fabaceae, in mice. Animal models of epilepsy namely the pentylenetetrazole, and maximal electroshock induced convulsion were used to evaluate the anticonvulsant effects of the extracts. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione. In the pentylenetetrazole induced convulsion, aqueous extract of D. triflorum 800 mg/kg significant delayed the onset of convulsion, reduced the duration of convulsion (p<0.05) and reduced mortality. The aqueous extract of D. triflorum 800 mg/kg dose reduced hind limb tonic extension phase of maximal electroshock induced convulsion induced convulsion in mice (p<0.05). The pretreated aqueous extract of D. triflorum showed significant inhibition of lipid peroxidation and increases the reduced glutathione level in mice brain tissue (p<0.001). The results revealed that D. triflorum possesses a significant dose dependent anticonvulsant activity.

Anticonvulsant activity of alcoholic root extract of Cardiospermum halicacabum

The aim of the present study was to evaluate the anticonvulsant effects of alcoholic root extract of Cardiospermum halicacabum L., Sapindaceae (ARECH), on the various murine models of epilepsy. The root extract of the plant was administered p.o. to male swiss albino mice at doses of 30, 100 and 300 mg/kg before evaluation. The brain monoamine levels were determined after two days administration. ARECH at doses of 100 and 300 mg/kg significantly delayed the onset of clonus and tonus in pentylenetetrazol, isoniazid and picrotoxin-induced convulsions. Tonic hind limb extension was also decreased at doses of 100 and 300 mg/kg as compared to vehicle control in maximal electroshock model. No significant motor toxicity was observed even at a highest dose administered, i.e. 900 mg/kg. Brain monoamine analysis by HPLC revealed a significant increase in GABAergic activity in C+ (in cerebellum) and C- (except cerebellum). These results suggested that ARECH possesses a significant anticonvulsant activity with a low motor toxicity profile. This activity may be attributed to an increase in GABAergic activity.

Evaluation of anticonvulsant activity of ethanolic leaves extract of Desmodium triflorum in mice

The present investigation was aimed to study an anticonvulsant activity of ethanolic extract of Desmodium triflorum (L.) DC., Fabaceae, in mice. Animal models of epilepsy namely the pentylenetetrazole (PTZ), isoniazid or isonicotinic hydrazide (INH) and maximal electroshock induced convulsion (MES) were used to evaluate the anticonvulsant effects of the extracts. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione (GSH). In the PTZ induced convulsion, ethanolic extract of D. triflorum (EEDT) 400 mg/kg significant delayed the onset of convulsion, reduced the duration of convulsion and reduced mortality. Similarly a dose of 800 mg/kg of EDDT significantly delayed the onset of convulsion, reduced the duration of convulsion and showed 33.33% protection in mice against INH induced convulsion. Further no mortality was found. Both the doses reduced hind limb tonic extension (HLTE) phase of MES induced convulsion in mice. The pretreated EEDT showed significant inhibition of lipid peroxidation and increases the reduced glutathione level in mice brain tissue. The results revealed that D. triflorum possesses a significant dose dependent anticonvulsant activity.

Anticonvulsant effect of the ethanol extract of Caesalpiniapulcherrima (L.) Sw., Fabaceae, leaves / Efeito anticonvulsivante do extrato etanólico das folhas de Caesalpinia pulcherrima (L.) Sw., Fabaceae

In this study, ethanol extract of Caesalpinia pulcherrima (L.) Sw., Fabaceae, leaves (CPEE) was investigated for anticonvulsant effect against maximal electroshock (MES) and pentylenetetrazole (PTZ) induced seizures in rats and mice at dose levels 200 and 400 mg/kg, i.p. respectively. Diazepam (3 mg/kg, i.p.) was used as a standard anticonvulsant drug for comparison. CPEE was found to be safe up to the dose of 4000 mg/kg in mice, when administered intraperitoneally. The extract at 400 mg/kg dose produced significant (p<0.01) anticonvulsant effect w.r.t. control against PTZ-induced clonic seizures. In MES-induced seizure model, there were no significant alterations in the onset as well as duration of hind limb extension seizures as compared to control at a dose of 200 mg/kg when administered intraperitoneally. However, the extract (CPEE, 400 mg/kg i.p.) significantly (p<0.01) delayed the onset as well as decreased the duration of hind limb extension seizures (HLES) as compared to control. However, the extract, CPEE, percentage protection of the animals was increased at higher dose (200 mg/kg) in both the models. The results of the study suggest that ethanol extract of Caesalpinia pulcherrima (L.) Sw. leaves possess anticonvulsant effect.

Neste estudo, foi investigada o efeito anticonvulsivante do extrato etanólico das folhas de Caesalpinia pulcherrima (L.) Sw., Fabaceae (CPEE), utilizando convulsões induzidas por eletrochoque máximo (MES) e pentilenetetrazol (PTZ), em ratos e camundongos, nas doses 200 e 400 mg/kg, i.p., respectivamente. Diazepam (3 mg/kg, i.p.) foi usado como uma droga anticonvulsivante padrão. O extrato (CPEE) foi seguro até a dose de 4000 mg/kg em camundongos, quando administrado por via intraperitoneal. O extrato de 400 mg/kg produziu efeito anticonvulsivante contra induções por PTZ de forma significativa (p<0,01). Em modelo de convulsão induzida por MES, não houve alterações significativas no início, bem como a duração das crises de extensão dos membros pélvicos em relação ao controle na dose de 200 mg/kg quando administrada por via intraperitoneal. No entanto, o extrato (CPEE, 400 mg/kg i.p.), de forma significativa (p<0,01), atrasou o início, como também diminuiu a duração das crises de extensão dos membros posteriores (HLES) em relação ao controle. O extrato (CPEE) aumentou a percentagem de proteção dos animais em dose maior (200 mg/kg) em ambos os modelos. Os resultados do estudo sugerem que o extrato etanólico de folhas de Caesalpinia pulcherrima (L.) Sw. possui efeito anticonvulsivante.