Maximal Electroshock Seizure Model Research Articles

DESIGN, SYNTHESIS, IN SILICO STUDIES, AND PHARMACOLOGICAL EVALUATION OF 5-ARYL-4-(CHLOROACETYLAMINO)-3-MERCAPTO-1,2,4-TRIAZOLE DERIVATIVES AS ANTICONVULSANT AGENTS

Objective: In this study, we reported the synthesis of a novel series of 5-aryl-4(chloroacetylamino)-3-mercapto-1, 2,4-triazoles. Methods: These compounds were synthesized to screen for anticonvulsant effects in a Maximal Electroshock Seizure (MES) model and a Subcutaneous Pentylenetetrazole (sc‐PTZ) seizure model in rats. Furthermore, molecular docking studies with gamma-aminobutyric acid and in silico ADME prediction were carried out to determine interactions of these compounds with Benzodiazepine (BZD) receptors and their similarity with standard drugs. The rotarod test was used to evaluate neurotoxicity. Results: 08 out of 40 compounds exhibited neurotoxicity at the maximum tested dose. Most of the compounds showed anti‐MES effects without any signs of neurological deficit. All the tested compounds significantly reduced seizures induced by PTZ compared to the control group. Carbamazepine and phenytoin were used as positive controls for anticonvulsant effects. Compounds 3d, 3h (a diphenylamine derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole), and 4a (a piperidinyl derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole) exhibited greater safety than phenytoin and carbamazepine in terms of neurotoxicity. The docking scores for the identified compounds 3d, 3h and 4a was 6.5133; 6.6558 and 5.6524, respectively. Nearly all the compounds (90%) demonstrated decreased locomotor activity. Conclusion: It is gratifying that the compounds with higher hydrophobicity showed better performance in the seizure models. Many triazole derivatives holding a suitable aryl or alkyl group gave a better anticonvulsant activity in their analogs.

In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation.

High fat diets have been used as complementary treatments for seizure disorders for more than a century. Moreover, many fatty acids and derivatives, including the broad-spectrum antiseizure medication valproic acid, have been explored and used as pharmacological agents to treat epilepsy. In this work, we have explored the anticonvulsant potential of a large library of fatty acids and fatty acid derivatives, the LIPID MAPS Structure Database, using structure-based virtual screening to assess their ability to block the voltage-gated sodium channel 1.2 (NaV1.2), a validated target for antiseizure medications. Four of the resulting in silico hits were submitted for experimental confirmation using in vitro patch clamp experiments, and their protective role was evaluated in an acute mice seizure model, the Maximal Electroshock seizure model. These four compounds were found to protect mice against seizures. Two of them exhibited blocking effects on NaV1.2, CaV2.2, and CaV3.1.

Effects of acute administration of 4-allyl-2,6-dimethoxyphenol in mouse models of seizures

Epilepsy, a chronic neurological disorder characterized by recurrent unprovoked seizures, presents a substantial challenge in approximately one-third of cases exhibiting resistance to conventional pharmacological treatments. This study investigated the effect of 4-allyl-2,6-dimethoxyphenol, a phenolic compound derived from various natural sources, in different models of induced seizures and its impact on animal electroencephalographic (EEG) recordings. Adult male Swiss albino mice were pre-treated (i.p.) with a dose curve of 4-allyl-2,6-dimethoxyphenol (50, 100, or 200 mg/kg), its vehicle (Tween), or standard antiepileptic drug (Diazepam; or Phenytoin). Subsequently, the mice were subjected to different seizure-inducing models – pentylenetetrazole (PTZ), 3-mercaptopropionic acid (3-MPA), pilocarpine (PILO), or maximal electroshock seizure (MES). EEG analysis was performed on other animals surgically implanted with electrodes to evaluate brain activity. Significant results revealed that animals treated with 4-allyl-2,6-dimethoxyphenol exhibited increased latency to the first myoclonic jerk in the PTZ and PILO models; prolonged latency to the first tonic-clonic seizure in the PTZ, 3-MPA, and PILO models; reduced total duration of tonic-clonic seizures in the PTZ and PILO models; decreased intensity of convulsive seizures in the PTZ and 3-MPA models; and diminished mortality in the 3-MPA, PILO, and MES models. EEG analysis indicated an increase in the percentage of total power attributed to beta waves following 4-allyl-2,6-dimethoxyphenol administration. Notably, the substance protected from behavioral and electrographic seizures in the PTZ model, preventing increases in the average amplitude of recording signals while also inducing an increase in the participation of theta and gamma waves. These findings suggest promising outcomes for the tested phenolic compound across diverse pre-clinical seizure models, highlighting the need for further comprehensive studies to elucidate its underlying mechanisms and validate its clinical relevance in epilepsy management.

Synthesis, Molecular Docking, and Anticonvulsant Activity of 1,3,4-Oxadiazole Derivatives

AbstractA novel series of 1,3,4-oxadiazoles (O1–4) were synthesized and physical characterization was done by spectroscopic data (infrared, mass, proton nuclear magnetic resonance). To ascertain the synthesized compound's likely binding mechanism and affinity toward the protein target (Protein Data Bank ID: 3R7X), molecular docking was performed. The synthesized compounds were subjected to in silico analysis using Schrodinger suite 2020–4 and absorption, distribution, metabolism, and excretion screening. Some of the synthesized compounds were subjected to in vivo evaluation of anticonvulsant activity by maximal electroshock seizure and pentylenetetrazol model. The synthesized 1,3,4-oxadiazole analogs may be developed as lead compounds and effective anticonvulsant agents for the pharmaceutical industry based on computational and in vivo data.

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and invivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For invivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. Invivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

PRAX-562-102: A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers (P4-9.011)

<h3>Objective:</h3> We report findings from a Phase 1 clinical trial characterizing the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PRAX-562 in healthy adults. <h3>Background:</h3> PRAX-562 is a next-generation sodium channel blocker with a unique profile expected to translate to a wider therapeutic window compared to current standard-of-care for severe DEE. <h3>Design/Methods:</h3> PRAX-562-102 was a randomized, placebo-controlled trial in healthy adults (18–55 years). Part A evaluated 90mg PRAX-562 over 28 days (QD) vs. placebo. Part B evaluated oxcarbazepine (OXC) in combination with 120mg PRAX-562 (QD) over 28 days vs. OXC alone. PD effects were examined on quantitative EEG (qEEG) and stimulated EEG (auditory steady state response, ASSR). <h3>Results:</h3> 48 participants were enrolled (Part A, n=18 PRAX-562, n=12 placebo; Part B, n=14 OXC+PRAX-562, n=4 OXC+placebo). PRAX-562 concentrations exceeded the EC₅₀ in the mouse maximal electroshock seizure (MES) model by 13-fold and was unaltered with OXC coadministration. PRAX-562 was generally well tolerated in Part A. TEAEs were mostly mild or moderate (100% Part A; 96% Part B). Part B was stopped early after 5 participants receiving OXC+PRAX-562 developed TEAEs; one of whom experienced 3 study drug-related SAEs leading to study drug discontinuation. Exposure-depended PD changes were observed on qEEG (all frequencies) and ASSR. Significant differences between placebo and PRAX-562 were observed in Part A on qEEG (Delta, <i>P</i>=0.0013; Theta, <i>P</i>&lt;0.0001) and ASSR (phase-locking-factor, <i>P</i>=0.028; Evoked power, <i>P</i>=0.016), and in Part B participants receiving OXC+PRAX-562 vs. OXC alone on qEEG (Delta, <i>P</i>=0.012; Theta, <i>P</i>=0.018). <h3>Conclusions:</h3> PRAX-562 was well tolerated in healthy adults at 90mg (Part A). Most AEs including SAEs in Part B were considered due to coadministration of projected supratherapeutic doses of PRAX-562 with OXC. Our PK and tolerability findings are consistent with a wide therapeutic window for PRAX-562, while PD findings indicate qEEG may be a sensitive translational biomarker of sodium channel blockade. <b>Disclosure:</b> Dr. Mahalingam has nothing to disclose. Dr. Oldham has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Puryear has received personal compensation for serving as an employee of Praxis Precision Medicine. Dr. Puryear has stock in Praxis Precision Medicines. Dr. Bansal has received personal compensation for serving as an employee of Praxis precision medicines . Dr. Bansal has stock in Praxis Precision medicines . Dr. Sriram has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Sriram has stock in Praxis Precision Medicines. Dr. Sriram has stock in Biogen Inc. Dr. Patel has received personal compensation for serving as an employee of Praxis Precision Medicines, Inc.. Dr. Patel has received personal compensation for serving as an employee of Noven Pharmaceuticals. Dr. Patel has stock in Praxis Precision Medicines, Inc.. Dr. Jacotin has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Jacotin has received personal compensation for serving as an employee of Takeda. Dr. Jacotin has stock in Takeda. Dr. Jacotin has stock in Certara. Dr. Jacotin has stock in Clover Health. Dr. Jacotin has stock in Coinbase. Marjie Hard has nothing to disclose. Dr. Arefayene has nothing to disclose. Dr. Ravina has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Ravina has stock in Praxis. Dr. Souza has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Souza has stock in Praxis Precision Medicines. Steven Petrou has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Praxis Precision Medicines. Steven Petrou has stock in Praxis Precision Medicines. The institution of Steven Petrou has received research support from Praxis Precision Medicines. The institution of Steven Petrou has received research support from Medical Research Future Fund. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care.

Nicorandil Exerts Anticonvulsant Effects in Pentylenetetrazol-Induced Seizures and Maximal-Electroshock-Induced Seizures by Downregulating Excitability in Hippocampal Pyramidal Neurons.

N-(2-hydroxyethyl) nicotinamide nitrate (nicorandil), a nitrate that activates adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, is generally used in the treatment of angina and offers long-term cardioprotective effects. It has been reported that several KATP channel openers can effectively alleviate the symptoms of seizure. The purpose of this study was to investigate the improvement in seizures induced by nicorandil. In this study, seizure tests were used to evaluate the effect of different doses of nicorandil by analysing seizure incidence, including minimal clonic seizure and generalised tonic-clonic seizure. We used a maximal electroshock seizure (MES) model, a metrazol maximal seizure (MMS) model and a chronic pentylenetetrazol (PTZ)-induced seizure model to evaluate the effect of nicorandil in improving seizures. Each mouse in the MES model was given an electric shock, while those in the nicorandil group received 0.5, 1, 2, 3 and 6mg/kg of nicorandil by intraperitoneal injection, respectively. In the MMS model, the mice in the PTZ group and the nicorandil group were injected subcutaneously with PTZ (90mg/kg), and the mice in the nicorandil group were injected intraperitoneally with 1, 3 and 5mg/kg nicorandil, respectively. In the chronic PTZ-induced seizure model, the mice in the PTZ group and the nicorandil group were injected intraperitoneally with PTZ (40mg/kg), and the mice in the nicorandil group were each given 1 and 3mg/kg of PTZ at a volume of 200nL. Brain slices containing the hippocampus were prepared, and cell-attached recording was used to record the spontaneous firing of pyramidal neurons in the hippocampal CA1 region. Nicorandil (i.p.) significantly increased both the maximum electroconvulsive protection rate in the MES model and the seizure latency in the MMS model. Nicorandil infused directly onto the hippocampal CA1 region via an implanted cannula relieved symptoms in chronic PTZ-induced seizures. The excitability of pyramidal neurons in the hippocampal CA1 region of the mice was significantly increased after both the acute and chronic administration of PTZ. To a certain extent, nicorandil reversed the increase in both firing frequency and proportion of burst spikes caused by PTZ (P < 0.05). Our results suggest that nicorandil functions by downregulating the excitability of pyramidal neurons in the hippocampal CA1 region of mice and is a potential candidate for the treatment of seizures.

Antiseizure Properties of Histamine H3 Receptor Antagonists Belonging 3,4-Dihydroquinolin-2(1H)-Ones.

H3R is becoming an attractive and promising target for epilepsy treatment as well as the discovery of antiepileptics. In this work, a series of 6-aminoalkoxy-3,4-dihydroquinolin-2(1H)-ones was prepared to screen their H3R antagonistic activities and antiseizure effects. The majority of the target compounds displayed a potent H3R antagonistic activity. Among them, compounds 2a, 2c, 2h, and 4a showed submicromolar H3R antagonistic activity with an IC50 of 0.52, 0.47, 0.12, and 0.37 μM, respectively. The maximal electroshock seizure (MES) model screened out three compounds (2h, 4a, and 4b) with antiseizure activity. Meanwhile, the pentylenetetrazole (PTZ)-induced seizure test gave a result that no compound can resist the seizures induced by PTZ. Additionally, the anti-MES action of compound 4a fully vanished when it was administrated combined with an H3R agonist (RAMH). These results showed that the antiseizure role of compound 4a might be achieved by antagonizing the H3R receptor. The molecular docking of 2h, 4a, and PIT with the H3R protein predicted their possible binding patterns and gave a presentation that 2h, 4a, and PIT had a similar binding model with H3R.

Design, Synthesis, and Pharmacology of New Triazole-Containing Quinolinones as CNS Active Agents.

Epilepsy and major depressive disorder are the two of the most common central nervous system (CNS) diseases. Clinicians and patients call for new antidepressants, antiseizure medicines, and in particular drugs for depression and epilepsy comorbidities. In this work, a dozen new triazole-quinolinones were designed, synthesized, and investigated as CNS active agents. All compounds reduced the immobility time significantly during the forced swim test (FST) in mice at the dosage of 50 mg/kg. Compounds 3f-3j gave superior performance over fluoxetine in the FST with more reductions of the immobility time. Compound 3g also reduced immobility time significantly in a tail suspension test (TST) at the dosage of 50 mg/kg, though its anti-immobility activity was inferior to that of fluoxetine. An open field test was carried out and it eliminated the false-positive possibility of 3g in the FST and TST, which complementarily supported the antidepressant activity of 3g. We also found that almost all compounds except 3k exhibited antiseizure activity in the maximal electroshock seizure (MES) model at 100 or 300 mg/kg. Compounds 3c, 3f, and 3g displayed the ED50 of 63.4, 78.9, and 84.9 mg/kg, and TD50 of 264.1, 253.5, and 439.9 mg/kg, respectively. ELISA assays proved that the mechanism for the antiseizure and antidepressant activities of compound 3g was via affecting the concentration of GABA in mice brain. The molecular docking study showed a good interaction between 3g and the amino acid residue of the GABAA receptor. Excellent drug-like properties and pharmacokinetic properties of compound 3a-l were also predicted by Discovery Studio. These findings provided a new skeleton to develop agents for the treatment of epilepsy and depression comorbidities.

The effects of cannabidiol and Δ9-tetrahydrocannabinol, alone and in combination, in the maximal electroshock seizure model

In the present study, cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and combinations of CBD and THC, were evaluated in the mouse maximal electroshock (MES) seizure test – an animal model of generalized-onset seizures. Male CF-1 mice were injected intraperitoneally (i.p.) with either CBD, THC or a combination of CBD and THC. The MES test was conducted 2 h after the injection of CBD and 1 h after the injection of THC. A wide range of doses was tested to allow the construction of dose-response curves. Toxicity was assessed using a behavioral rating scale. It was found that: 1) the ED50 for THC alone was 52 mg/kg and its therapeutic index (TI) was 1.7; 2) the ED50 for CBD alone was 190 mg/kg and its TI was 2.4; and 3) the ED50 for a 15:1 combination of CBD+THC was 130 mg/kg + 8.6 mg/kg (CBD + THC). Thus, CBD and THC were both effective in the MES model, and CBD was somewhat more effective in the presence of low (non-therapeutic) doses of THC. The improvement in CBD’s effect, however, was less dramatic than that seen in past experiments with the amygdala-kindling model (Fallah et al., 2021). Both CBD alone and CBD+THC in combination might be useful in the treatment of generalized-onset seizures. The advantage of adding THC to CBD, however, might be less than in the treatment of focal-onset seizures.

In vitro and in vivo anti-seizure activity of hydromethanolic extract and fractions of Pterolobium stellatum

Ethnopharmacological relevanceIn Ethiopia, the whole plant juice of Pterolobium stellatum is used to treat seizures and epilepsy. Aim of the studyTo investigate the antiseizure activity of hydromethanolic crude extract and fractions collected from leaves of P. stellatum using both in vitro, and in vivo seizure models in mice. Materials and methodsFresh leaves of P. stellatum were collected from Awash Melka, Addis Ababa, Ethiopia. An 80% crude methanol extract was further fractionated to produce petroleum ether, chloroform, butanol, and aqueous fractions. Anti-seizure activity of the crude extract and fractions (petroleum ether, chloroform, butanol, and water) were assessed at a concentration of 0.7 mg/ml using the in vitro 0 Mg2+ model of seizures in mouse brain slices prepared from 14- to 21-day-old C57BL/6 mice. The maximal electroshock seizure (MES) model and the pentylenetetrazol (PTZ) seizure model for seizures were performed on male BALB/c mice using 400 mg/kg and 800 mg/kg of crude 80% methanol extract, as well as the four fractions described above. Diazepam and phenytoin were used as positive controls for PTZ and MES test respectively. ResultsAddition of 0.7 mg/ml of crude 80% methanol extract of P. stellatum prevented the onset of SLEs in most brain slices in the 0 Mg2+in vitro model of seizures, with similar efficacy to diazepam (3 μM). The same extract at 400 and 800 mg/kg was efficacious in reducing the hindlimb extension time in the MES model and delaying the onset of myoclonic convulsions in the PTZ model, although not to the same extent as phenytoin (10 mg/kg) or diazepam (5 mg/kg). The chloroform and water fractions of the crude extract also showed significant anti-seizure activity across all three models whilst the non-polar petroleum ether and butanol fractions did not. The UPLC-MS analysis indicated the presence of gallic acid, ellagic acid, kaempferol, myricitrin, isoquercitrin and quercitirin in the crude extract. Gallic acid and ellagic acid were observed in chloroform fraction and in the water fraction ellagic acid, kaempferol, myricitrin and isoquercitrin were detected. ConclusionThe crude hydromethanolic extract of P. stellatum has significant anti-seizure activity. The chloroform and aqueous fractions have antiseizure activity. The extracts have previously identified compounds with anticonvulsant activity which indicates the antiseizure potential of the plant.

Low-Dose Digoxin is Associated with Anticonvulsant Effect Enhancement of Classical Antiepileptic Drugs in the Electro-Induced Seizures in Mice

The aim of the study was to determine the effect of low doses of cardiac glycoside digoxin on the anticonvulsant effect of five classical antiepileptic drugs, sodium valproate, topiramate, levetiracetam, clonazepam and phenobarbital, under experimental seizures in mice. Antiepileptic drugs were administered 30 min before to 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; phenobarbital – at doses of 20 and 10 mg/kg; clonazepam – at doses of 0.1 and 0.05 mg/kg body weight. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10-15 min before seizure induction. Maximal electroshock seizure model was reproduced by transmitting an electric current (strength – 50 mA, frequency – 50 Hz) through the corneal electrodes for 0.2 sec. It was found that low-dose digoxin potentiates the anticonvulsant effects of sodium valproate, topiramate and phenobarbital as well as modulates the effects of levetiracetam and clonazepam, showing a distinct pharmacological effect of their sub-effective doses and increasing their therapeutic potential even under incomplete seizure control – the equivalent of drug-resistant epilepsy. The obtained results substantiate the expediency of further study of digoxin as an anticonvulsant drug in the adjuvant therapy of epilepsy and other seizure conditions.

Anticonvulsant activity of 2-amino-4-chloro-6-methyl pyrimidine derivatives: synthesis and characterization

A series of new 2-amino-4-chloro-6-methylpyrimidine derivatives, 3(a-f) was synthesized by using different aryl aldehydes. The synthesized compounds were characterized by FT-IR and 1H NMR spectral studies. The maximal electroshock seizure (MES) model was used for anticonvulsant activity and phenytoin was used as standard drug. The rotorod test for neurotoxic effects was determined. Compound 3e was found to be most potent of this series. The compound 3e showed 65.10% protection in comparison to phenytoin which completely inhibited the convulsions produced by electro-convulsometer, Similarly, compound 3a showed moderate protective effects.

Anticonvulsant Activity of Lacidipine against Mes- and Ptz-Induced Seizures

Epilepsy is one of the challenging medical conditions affecting neonates, children and elderly. It has affected 1710 to 9780/million populations within India. Although the report of this condition dates to the prehistoric era, drugs for its treatment are not 100% effective and more often lead to toxic effects. Therefore, a potent drug or a drug adjunct is the need-of-the-hour for providing effective control for this neurological condition. The aim of the present study is to evaluate lacidipine, a calcium channel blocker as a protective agent in seizures induced by standard models of epilepsy, namely maximal electroshock seizure model (MES) and Pentylenetetrazole (PTZ). Standard methods for the induction of seizures such as MES and PTZ were performed on male Wistar albino mice. The mice were then treated with vehicle/standard drug (sodium valproate)/ lacidipine. Further, the standard parameters of recovery duration were evaluated. The study revealed that lacidipine at a dose of 3mg/kg body weight significantly reduced the duration of hind limb tonic extension and postictal depression in MES. PTZ-induced seizures showed significantly reduced mean duration of hind limb tonic flexion, hind limb tonic extension, clonus and postictal depression. The findings from the present study suggest that lacidipine has potent anticonvulsant ability in better protection against MES-induced seizures over that of the PTZ-induced one.

The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers.

ObjectiveThis study investigates the effects of PRAX‐562 on sodium current (INa), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent INa inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage‐gated sodium channel (NaV) blockers.MethodsInhibition of INa was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA).ResultsPRAX‐562 potently and preferentially inhibited persistent INa induced by ATX‐II or the SCN8A mutation N1768D (half‐maximal inhibitory concentration [IC50] = 141 and 75 nmol·L–1, respectively) relative to peak INa tonic/resting block (60× preference). PRAX‐562 also exhibited potent use‐dependent block (31× preference to tonic block). This profile is considerably different from standard NaV blockers, including carbamazepine (CBZ; persistent INa IC50 = 77 500 nmol·L–1, preference ratios of 30× [tonic block], less use‐dependent block observed at various frequencies). In contrast to CBZ, PRAX‐562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX‐562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half‐maximal efficacious concentration = 4.3 nmol·L–1, sLMA half‐maximal tolerated concentration = 69.7 nmol·L–1, protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity.SignificancePRAX‐562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX‐562 exhibited significantly improved preclinical tolerability compared with standard NaV blockers (CBZ and LTG), potentially due to the preference for persistent INa. Preferential targeting of persistent INa may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard NaV blockers have demonstrated efficacy but poor tolerability.

Pharmacophore Based Design, Synthesis and Theoretical Conformational Analysis of Some Extended Aryl Hydrazones as Potential Anticonvulsant

A series of hydrazones were synthesized by condensing substituted hydrazides with appropriate carbonyl compounds. The chemical structures of the synthesized compounds were confirmed by infrared, proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, mass ((4-chloro-phenylamino)-acetic acid [1-(4-chlorophenyl)-phenyl-methylene]-hydrazide and (2,4-dichloro-phenylamino)-acetic acid (3-oxo- 1,3-dihydro-indole-2-ylidene)-hydrazide only) spectral data and carbon hydrogen nitrogen analysis. The title compounds were screened for their anticonvulsant activity against mice at doses of 30 mg/kg, 100 mg/kg and 300 mg/kg. The preliminary anticonvulsant screening data of this series resulted in the identification of two lead compounds (2,4-dichloro-phenylamino)-acetic acid (3-oxo-1,3-dihydro-indole- 2-ylidene)-hydrazide and (2,4-dichloro-phenylamino)-acetic acid [1-(4-chlorophenyl)-phenyl-methylene]- hydrazide with excellent preliminary anticonvulsant profile with no neurotoxicity in maximal electroshock seizure and subcutaneous metrazol mice model.

Evaluation of Antiepileptic activity of Mosapride in Albino wistar rats

Serotonin causes a significant shift in the excitability of neurons and endogenous serotonin and drugs acting on serotonergic receptors play a role in pathogenesis of epilepsy. This study was done to study the effect of Mosapride, a serotonin receptor 5HT4 agonist, in animal models of epilepsy. Albino Wistar rats were divided into 5 groups with six animals in each group. Group 1 was control group, group 2 was standard group and group 3, 4 and 5 received test drug mosapride in low dose (3mg/kg), high dose (6mg/kg) and mosapride plus standard antiepileptic drug respectively. The antiepileptic efficacy was evaluated using Maximal Electroshock Seizure model (MES) and Pentylenetetrazole (PTZ) induced convulsions. Data was analysed using ANOVA followed by post hoc Tukeys test. Mosapride treated animals showed statistically significant decrease (p&lt;0.001) in the duration of flexion, hind limb extension and post ictal depression in MES model which was comparable to phenytoin group. In PTZ model, mosapride alone did not show any significant difference as compared to control group in terms of latency and duration of seizures (p&gt;0.05). The antiepileptic efficacy of mosapride is similar to phenytoin in MES model. However, in PTZ model mosapride did not show any beneficial antiepileptic effect

Anticonvulsant activity of methanolic extract of Withania cogulans in mice

Mental and neurological diseases including depression, Parkinson's disease, dementia, epilepsy, anxiety disorders and bipolar disorders account for a considerable amount of the world's disease burden. Unfortunately, drugs used in the treatment of neurological diseases are expensive, symptomatic and they produce undesirable side effects. People from different cultures prefer to use medicinal plants for the treatment of various ailments ranging from plain to perplex disorders because they are most affordable, cost effective and easily accessible source of treatment in the primary healthcare system throughout the world. Withania coagulans, an erect grayish under-shrub belongs to family Solanaceae. It is common in Pakistan, East India, Iran and Afghanistan. The objective of this study was to analyze the anti-seizure activity of crude methanolic extract of Withania coagulans fruits (MeWc). For screening of this activity, maximal electroshock seizures model (MES) and chemically-induced seizures models were used. In maximal electroshock seizures test MeWc showed significant dose dependent percent protection against hind-limb tonic extension; significant and dose-dependent increase in latency to myoclonic jerks and tonic clonic convulsions and decrease in seizures duration were observed in PTZ-induced seizures. In strychnine-induced convulsions MeWc significantly increased latency to hind-limb tonic extension and percent protection from death in a dose-dependent manner. Thus, it was inferred from the experiments that extract of Withania coagulans showed anticonvulsant activity.

Synthesis and Anticonvulsant Evaluation of 3-(5-(4-substitutedphenyl)-4,5-dihydro-1H-pyrazol- 3-ylamino)-2-(2-methylphenyl)quinazolin-4(3H)-one Derivatives

Abstract: Epilepsy arise due to discharge of electric current in CNS and it is Characterized by repeated seizure because of different factors like social, neurological and environmental or it may be due to genetic or non-genetic. A large number of AED’s used to treat epilepsy but all these shows drug resistance and side effects, so research interest continue to find out novel antiepileptic drugs with higher efficiency and less toxicity.A novel series of 3-(5-(4-substitutedphenyl)-4,5-dihydro-1H-pyrazole-3-ylamino)-2-(2-methylphenyl) quinazole4(3H)-one was developed, synthesized and evaluated for anticonvulsant activity using two pharmacological models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models. Spectral data and elemental analysis were used to validate the structure of the synthetic compounds. Synthesized substances have also been tested for their neurotoxicity by rotary apparatus. Both compounds display strong anticonvulsant and neurotoxic activity. 3-(5-(4-fluorophenyl)-4,5-dihydro- 1H-pyrazole-3-ylamino)-2-(2-methylphenyl)quinazole-4(3H)-one, 8(v) was found to be the most successful in maximal electroshock seizure (percentage protection = 73.63 at 150 mg/kg) and subcutaneous pentylenetetrazole induced convulsion model (percentage protection = 75.59 at 150 mg/kg) models and was found to be non-neurotoxic. Key words: AED’s, Qinazolin-4-(3H)-one, Anticonvulsant, MES, scPTZ, Neurotoxicity.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats

Ethnopharmacological relevanceCentella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. Aim of the studyThe present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. Materials and methodsWistar rats (175–200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. ResultsThe VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. ConclusionThe results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.