Rationale design, synthesis, and pharmacological evaluation of isatin analogues as antiseizure agents

Background: Epilepsy is one of the most common and devastating neurological disease affecting about 1% of the world’s population at any time. Herein, we have reported rationale design and synthesis of 5-acetyl-3-((4-substitutedphenyl)imino)indolin-2-one analogues 3(a-k) as antiseizure agents. Objective: These analogues were designed as four component pharmacophoric model by clubbing structural fragments of potent antiepileptic drugs. Aim of this study was to synthesize structurally designed isatin analogues and screened them for anticonvulsant activity and neurotoxicity. Methods: Designed derivatives were synthesized using bulky scale feasible and inexpensive microwave methodology. All the synthesized compounds were then characterized by multiple spectroscopic techniques and screened for anticonvulsant activity through preclinical in-vivo experiments. Results: The compound 3d have exhibited good anticonvulsant activity in preclinical seizure models with better toxicity profile when compared to standard drugs (3d: ED50 = 31.5 mg/kg, MES test; ED50 = 37.4 mg/kg, scPTZ test; TD50 = 384.3 mg/kg,). Compound 3d have also shown good binding affinity at crucial amino acids of GluN1 subunit of NMDAR (Docking score = -9.30) and fit adequately in the cavity of receptor (Amino acids involved and H-bonding distance = GLY93: acetyl >C=O, 2.38Å; PHE92: acetyl >C=O, 2.22Å; and THR26: >C=O of isatin, 1.71Å). Results of molecular docking supported the structural features present over isatins to persuade potent antiseizure activity. Conclusion: Rationale designing strategy, in-vivo pharmacological profile, and computational studies make us to anticipate the emergence of these molecules as novel antiseizure agents which can be further explored to develop probes for the treatment of epilepsy.

C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.

The Screening models for antiepileptic drugs: A Review

Considering the prevalence of epilepsy and the problems associated with currently available antiepileptic drugs like side effects, resistance, safety issue and high cost, herbal medicine with fewer complications could be very appropriate alternative. Therefore in the present study, we have examined the antiepileptic properties of ethanolic extract of leaves in mice using maximal electroshock seizers (MES)test, Pentylenetetrazole (PTZ), induced seizures, strychnine induced convulsion, Isoniazid-induced convulsions, Picrotoxin-induced convulsions, Kainic acid (KA) model etc.There is increased concern on agents for epilepsy disease modification and prevention. To solve these unmet needs, the research scientist must have a thorough knowledge of available animal models of epilepsy so that he can pick up the best model for his research. In this article, we are reviewing the diversity of animal models of epilepsy and their implications in antiepileptic drug discovery. Keywords: Epilepsy, animal model, seizures,

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives

We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED50 values in the range of 19–39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED50 value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED50 values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action.

Synthesis, Anticonvulsant, and Antinociceptive Activity of New 3-(2-Chlorophenyl)- and 3-(3-Chlorophenyl)-2,5-dioxo-pyrrolidin-1-yl-acetamides

The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione (6) showed more beneficial ED50 and protective index values than the reference drug—valproic acid (68.30 mg/kg vs. 252.74 mg/kg in the MES test and 28.20 mg/kg vs. 130.64 mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds—namely, 6 and 19—was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABAA and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound 6 relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds 6 and 19 were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect.

How Antidepressant Drugs Affect the Antielectroshock Action of Antiseizure Drugs in Mice: A Critical Review

Depression coexists with epilepsy, worsening its course. Treatment of the two diseases enables the possibility of interactions between antidepressant and antiepileptic drugs. The aim of this review was to analyze such interactions in one animal seizure model—the maximal electroshock (MES) in mice. Although numerous antidepressants showed an anticonvulsant action, mianserin exhibited a proconvulsant effect against electroconvulsions. In most cases, antidepressants potentiated or remained ineffective in relation to the antielectroshock action of classical antiepileptic drugs. However, mianserin and trazodone reduced the action of valproate, phenytoin, and carbamazepine against the MES test. Antiseizure drug effects were potentiated by all groups of antidepressants independently of their mechanisms of action. Therefore, other factors, including brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) modulation, should be considered as the background for the effect of drug combinations.

Anticonvulsant Effect of Nebivolol alone and in Combination with Phenytoin against Maximal Electroshock-Induced Seizures in Mice

Introduction: Phenytoin is widely used in treatment of generalised tonic clonic seizures but its adverse effects make its usage limited. Hence forth, there is a need for newer antiepileptics. Studies have shown antiepileptic property for nebivolol in combination with phenytoin hence, reducing the dosage of phenytoin and its adverse effects and toxicities. Aim: To evaluate the anticonvulsant property of nebivolol alone and in combination with phenytoin against Maximal Electroshock Seizures (MES) in a mouse model. Materials and Methods: This was an experimental animal study on total of 36 swiss albino male mice were randomly assigned to six groups with six animals in each group in December 2019 at Sri Manakula Vinayagar Medical College and Hospital. Group 1 was considered as normal control, Group 2 received Phenytoin 25 mg/kg Intraperitoneal (IP); Group 3 & 4 received Nebivolol 0.25 mg/kg oral & 0.50 mg/kg oral, respectively; Group 5 received 12.5 mg/kg IP and nebivolol 0.25 mg/kg oral; Group 6 received Phenytoin 12.5 mg/kg IP and nebivolol 0.50 mg/kg oral. Anticonvulsant effect of the drugs nebivolol and phenytoin was elicited in mice by MES test. After induction following parameters were recorded for onset of Tonic Hind Limb Extension (THLE), duration of clonus, duration of THLE, number of jerks, recovery time. Statistical analysis was done by ANOVA followed by post-hoc Dunnett t-test. Results: Significant reduction in duration of THLE (p<0.01) and clonus (p<0.001) was observed in the group treated with phenytoin (12.5 mg/kg) and nebivolol (0.50 mg/kg). Conclusion: The present study concludes that the lower dose of phenytoin in combination with nebivolol can reduce seizures induced by MES in mice model.

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.