Pharmacological Activity of Pyrazole Derivatives as an Anticonvulsant for Benefit against Epilepsy

<b><i>Introduction:</i></b> Pediatric patients with epilepsy are prone to cognitive impairments during growth and long-term use of most antiepileptic drugs (AED). The affected children do not respond to conventional AED and may require novel drugs to manage the disease. Valproic acid, a first-line drug to treat epilepsy, is associated with serious side effects, which precludes its wider use. Thus, in the present study, we intended to develop novel substituted pyrazoles. <b><i>Methods:</i></b> The molecules were tested for anticonvulsive activity in Swiss albino mice via maximal electroshock seizure and subcutaneous pentylenetetrazole assays. The most potent molecule among the class was further assayed for its effect on behavioral and CNS depressant activity. The effect of the most potent compounds was also analyzed on various indices of oxidative stress and inflammation in mice. <b><i>Results:</i></b> The designed compounds showed significant anticonvulsive activity in mice revealing 7h as the most potent anticonvulsive agent. The most potent anticonvulsant molecule 7h further showed no behavioral alteration and considerable CNS depressant activity. It also reduces the level of oxidative stress and inflammation in the mice. <b><i>Conclusion:</i></b> Our study demonstrated utility of pyrazole derivatives as anticonvulsants against epilepsy.

Screening Study for Anticonvulsive Activity of Lipophilic Fractions from Empetrum nigrum L.

Introduction: The plants of genus Empetrum, which are used in the traditional medicine to cure seizures and neurodegenerative diseases, can be considered as potent antiepileptic drugs. This paper focuses on a comparative analysis of an anticonvulsive activity of lipophilic fractions from Empetrum nigrum L. Materials and methods: The experiments were conducted using mature outbred CD-1 male mice. The lipophilic fractions from aerial parts of Empetrum nigrum L. were administered through a catheter into the stomach at a dose of 150 mg/kg for 5 days. The anticonvulsive effects were studied using the acute seizure tests: strychnine-, pentylenetetrazole – and maximal electroshock (MES) induced tests. Carbamazepine was used as a positive control drug at a dose of 100 mg/kg. Results and discussion: The acetone-soluble fraction (ASF) of the chloroform extract from Empetrum nigrum L. showed a pronounced anticonvulsive effect on seizures induced by strychnine (1.5 mg/kg) and pentylenetetrazole (150 mg/kg). In comparison to the control group, the time from seizures to death increased by 1.5 for the strychnine-induced seizures, and 1.9 times in case of pentylenetetrazole model. The survival rate of the animals was 22.2% and 20%, correspondingly. The survival rate in the MES test was 77.8%. Overall, ASF demonstrates a remarkable anticonvulsive activity in all the tests, especially in the MES test. Conclusion: Our study for the first time shows a potent antiepileptic effect of ASF from Empetrum nigrum L., containing triterpene compounds and chalcones. The future studies will be focused on investigating the exact mechanisms of anticonvulsive and neuroprotective effects of ASF.

Potentiation of anticonvulsant effect of phenytoin by celecoxib against maximum electroshock induced convulsions in albino rats

Background: Epilepsy, a chronic neurological disorder affects more than 1% of world population. Despite the availability of a number of antiepileptics, refractoriness to them exists in approximately one third of cases worldwide. Induction of cycloxygenase and increased levels of proinflammatory meditators are seen in epilepsy. P-glycoprotein upregulation due to phenytoin was found to contribute to its pumping out of cell, leading to refractoriness to phenytoin therapy. Also, cycloxygenase-2 inhibitors were found to prevent P-glycoprotein upregulation. Since cycloxygenase-2 inhibition decreases levels of proinflammatory cytokines responsible for neuroinflammation, this study aims to evaluate anticonvulsant effect of celecoxib and also to investigate whether it potentiates the anticonvulsant effect of phenytoin.Methods: Maximum electroshock seizures (MES) were induced in Albino rats using electroconvulsiometer to evaluate tonic convulsions, identified by tonic hind limb extension (THLE) in rats. A delay in onset of THLE and a reduction in duration of THLE were taken as deciding parameters to ascertain anticonvulsive activity. Rats randomly divided into groups, received pretreatment with celecoxib at 3 doses (10, 20, 40 mg/kg), phenytoin (6.25 mg/kg), phenytoin (12.5 mg/kg) and combination of phenytoin (6.25 mg/kg) with celecoxib (ED50, i.e. 20 mg/kg), before inducing MES seizures and findings compared to control group.Results: Celecoxib (20 and 40 mg/kg) showed significant anticonvulsant effect by MES test. Also, its combination with phenytoin caused significant decrease in the duration of THLE when compared to phenytoin alone at the same dose.Conclusions: The results of this study indicate that celecoxib potentiates the anticonvulsant effect of phenytoin.

Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration

Background The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice. Methods VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured. Results After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration. Conclusions The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.