Electroshock-induced Seizures Research Articles

Potential Mechanisms Involved in the Anticonvulsant Effect of Recombinant Human VEGF on Maximal Electroshock-induced Seizure

Background: Vascular endothelial growth factor (VEGF) signaling pathway plays an important role in the pathogenesis of seizure. The oxidant/antioxidant factors and miRNA expression in the brain are differentially regulated in seizure. Objectives: We aim to investigate the potential mechanism of action for the recombinant human VEGF (rhVEGF) in mice with maximal electroshock (MES)-induced seizure. Materials & Methods: A total of 40 male mice (weight: 20-25 g) were treated intraperitoneally with normal saline, or rhVEGF (50, 100, and 150 µg/kg, daily for 4 consecutive days). One hour after the last injection, seizures were induced in each animal by MES. The latency for the onset of the first clonus and the duration of hind limb extension (HLE) were recorded. The levels of nitric oxide (NO), total antioxidant capacity (TAC), and micoRNA-142-5p expression were determined in the hippocampus of mice. Blood-brain barrier (BBB) permeability was also estimated by Evans blue dye extravasation method. Results: The administration of rhVEGF at all doses significantly reduced the HLE duration. However, latency for the seizure onset increased after administration of 50 and 150 μg/kg rhVEGF and decreased after administration of 100 μg/kg rhVEGF. In the brain, the NO level decreased, while TAC level and microRNA-142-5p expression increased by rhVEGF treatment in mice with MES-induced seizure. Pretreatment with rhVEGF at doses of 100 and 150 μg/kg reversed the increase in BBB leakage induced by MES-induced seizures. Conclusion: The rhVEGF administration can prevent MES-induced seizures by regulating NO, TAC, and miR-142-5 expression levels in the hippocampus and reducing BBB leakage in mice.

Comparative Analysis of Anticonvulsant Activity of Trans and Cis 5,5'-Diphenylhydantoin Schiff Bases.

Recently, the four 5,5'-diphenylhydantoin Schiff bases, possessing different aromatic species (SB1-Ph, SB2-Ph, SB3-Ph and SB4-Ph) were synthesized, characterized, and evaluated for anticonvulsant activity in combination with phenytoin. In the present study, the SB1-Ph and SB4-Ph compounds were selected, based on their anticonvulsant potency, and compared with their cis isomers, prepared after a one-hour exposure to the UV source, for their anticonvulsant potency in the maximal electroshock (MES) test and the kainate (KA)-induced status epilepticus (SE) test in mice. In the MES test, the cisSB1-Ph compound exhibited superior to phenytoin and trans isomer activity in the three tested doses, while the cisSB4-Ph compound entirely suppressed the electroshock-induced seizure spread at the highest dose of 40 mg/kg. Pretreatment with the cisSB1-Ph compound and the cisSB4-Ph at the doses of 40 mg/kg, respectively, for seven days, significantly attenuated the severity of KA SE compared to the matched control group pretreated with a vehicle, while phenytoin was ineffective in this test. The cisSB4-Ph but not the cisSB1-Ph demonstrated an antioxidant effect against the KA-induced SE in the hippocampus. Our results suggest that trans-cis conversion of 5,5'-diphenylhydantoin Schiff bases has potential against seizure spread in the MES test and mitigated the KA-induced SE. The antioxidant potency of cisSB4-Ph might be associated with its efficacy in mitigating the SE.

Pharmacognostic profiles, evaluation of analgesic, anti-inflammatory and anticonvulsant activities of Newbouldia laevis (P. Beauv.) Seem. ex Bureau leaf and root extracts in Wistar rats

Ethnopharmacological relevanceNewbouldia laevis is a popular medicinal plant whose leaves and roots are used in Nigeria as ethnomedicinal prescriptions for pain, inflammation, convulsion, and epilepsy. These claims have not been scientifically verified prior to this study. Aim of the studyTo determine pharmacognostic profiles of the leaves and roots and evaluate the analgesic, anti-inflammatory, and anticonvulsant activities of methanol leaf and root extracts in Wistar rats. Material and methodsThe pharmacognostic profiles of the leaves and roots were determined using standard procedures to serve as fingerprints for the plant. The methanol leaf and root extracts of Newbouldia laevis were tested for acute toxicity using the OECD’s up and down method at the maximum dose of 2000 mg/kg (orally) in Wistar rats. Analgesic studies were carried out in acetic acid-induced writhing in rats and tail immersion. The anti-inflammatory activity of the extracts was evaluated using carrageenan-induced rat paw-oedema and formalin-induced inflammation in rats’ mode. The anticonvulsant activity was determined using strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced rat convulsion models. For each of these studies, the extracts doses of 100, 200 and 400 mg/kg were administered to the rats following the oral route. ResultsThe pharmacognostic profiles showed that the leaves possessed deep-sunken paracytic stomata (5-8-16 mm2; adaxial, 8-11-24 mm2; abaxial epidermis), vein islets (2-4-10 mm2; adaxial), vein terminations (10-14-18 mm2; adaxial), palisade ratio (8.3-12.5-16.4 mm2; adaxial, 2.5-6.8-12.2 mm2; adaxial), covering unicellular trichome (8–14; adaxial), spheroidal calcium oxalate crystals (3–5 μm), and oval-shaped striated starch grain with no hilum (0.5–4.3 μm). The transverse section of the leaf showed the presence of spongy and palisade parenchyma as well as a closed vascular bundle. The root powder showed the presence of brachy sclereid, fibers without lumen, and lignin. All physicochemical parameters fall within the acceptable limits, phytochemical contents showed mainly glycosides, alkaloids, and steroids while acute oral toxicity (LD50) of the parts for 14 days did not produce any toxicity signs or mortality in the rats. The extracts produced dose-dependent (100–400 mg/kg) analgesic involving opioid receptors, anti-inflammatory, and anticonvulsant activities in the rats which were significant (p ≤ 0.05) when compared to the standard drugs. The leaf extract possessed the most potent analgesic and anti-inflammatory effects in the rats, while the most anticonvulsant effects were observed in rats treated with the leaf extract. Both extracts showed elevated levels of protection against strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced seizure in rats. ConclusionOur study revealed some pharmacognostic profiles of Newbouldia laevis leaves and roots that are vital for its identification from closely related species often used for adulteration in traditional medicine. The study further showed that the leaf and root extracts of the plant possessed dose-dependent analgesics, anti-inflammatory and anti-convulsant activities in rats, thus, justifying its use for the treatment of these diseases in Nigerian traditional medicine. There is a need to further study its mechanisms of action towards drug discovery.

Evaluation of the Effect of Pheophytin A on Electroshock- Induced Seizures in Experimental Animals

Abstract: Background: An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Approximately, 5–10% of the people have at least one kind of seizure, with more chance of occurrence in early childhood and late adulthood. There are many drugs used in seizures such as phenytoin and valproate sodium, so the main objective of current study was evaluated the efficacy of Pheophytin A compared to Valproate sodium on electroshock-induced seizures in experimental mice. Materials and Methods: The total number of 18 mice were used after divided into 3 groups in which each group was 6 mice. The first group, which is control, was received injection with distilled water. The second group was standard reference which received valproate sodium at dose of 300 mg/kg. The third group was test group which received 20 mg /kg of pheophytin A. Maximum electrical shocker was used to induce seizures. Results: The present study showed that pheophytin-A group had significantly reduced duration of seizures after 30 min of injection as compared to valproate sodium group. Valproate sodium produced more reduction in duration of seizures than pheophytin-A. Conclusion: The Pheophytin A showed antiseizure effect using maximal electrical shocker, so that it may be used in the future for treatment of seizures after further investigations. Keywords: Seizures, Pheophytin A, Valproate sodium, Maximal electroshock seizure, In vivo.

Interaction of Varenicline with Classic Antiseizure Medications in the Mouse Maximal Electroshock-Induced Seizure Model.

Varenicline (VAR) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors recommended as a first line pharmacotherapy for smoking cessation. The aim of this study was to examine whether VAR affects the protective activity of four classic antiseizure medications, i.e., carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) on maximal electroshock (MES)-induced seizures, which may serve as an experimental model of human-generalized tonic-clonic seizures in mice. VAR administered intraperitoneally (i.p.) at a subthreshold dose of 0.5 mg/kg decreased the protective activity of CBZ against MES-induced convulsions, increasing its median effective dose (ED50) from 10.92 ± 1.0 to 18.15 ± 1.73 mg/kg (p < 0.01). The effect of VAR was dose-dependent because a lower dose of VAR (0.25 mg/kg) failed to antagonize the protective activity of CBZ. VAR administered at the subthreshold dose of 0.5 mg/kg had no impact on the protective activity of PB, PHT, and VPA in the mouse MES model. The inhibitory effect of VAR on the protective activity of CBZ against tonic-clonic convulsions most likely resulted from the pharmacodynamic mechanism(s) and was not associated with the changes in total brain concentrations of CBZ. VAR-evoked alterations in the anticonvulsive activity of CBZ may be of serious concern for epileptic tobacco smokers.

Insulin potentiates the anticonvulsive activity of phenytoin against maximal electroshock-induced seizures in mice.

The limitations imposed by the blood-brain barrier (BBB) on the sufficient accumulation of antiepileptic drugs (AEDs) in the epileptogenic focus is considered the major cause of the high percentage of morbidity and mortality cases among epilepsy patients. This study aimed at examining the potential effect of insulin on the anticonvulsant action of phenytoin (PHT) in the mouse maximal electroshock-induced seizure model. PHT was administered orally in single doses either alone or in combination with insulin given as single intraperitoneal injections. To assess the anticonvulsant activity of PHT, the ED50 values were calculated. The current strength (CS50) threshold for insulin was also estimated. The animals were sacrificed, and the brains were removed to measure their PHT concentrations in the brain. It has been demonstrated that insulin (in all used doses) has no effect on the CS50 but can cause a significant increase in concentrations of PHT in the brain and potentiate the antiepileptic efficiency of this drug in electroshock-induced models of epilepsy in mice. The combination of insulin with PHT may be of great importance for developing new treatment possibilities following further investigations with otheranimal models of epilepsyandpreclinical studies. Further research is also needed to explore the concentrations of PHT in the brain and the anticonvulsant activity of this drug against maximal electroshock seizures in diabetic mice.

Anticonvulsant effects of ivermectin on pentylenetetrazole- and maximal electroshock-induced seizures in mice: the role of GABAergic system and KATP channels

IntroductionIvermectin (IVM) is an antiparasitic medicine that exerts its function through glutamate-gated chloride channels and GABAA receptors predominantly. There is paucity of information on anti-seizure activity of IVM. Moreover, the probable pharmacological mechanisms underlying this phenomenon have not been identified. Materials and methodsIn this study, pentylenetetrazole (PTZ)-induced clonic seizures and maximal electroshock (MES)-induced tonic-clonic seizure models, respectively in mice was utilized to inquire whether IVM could alter clonic seizure threshold (CST) and seizure susceptibility. To assess the underlying mechanism behind the anti-seizure activity of IVM, we used positive and negative allosteric modulators of GABAA (diazepam and flumazenil, respectively) as well as KATP channel opener and closer (cromakalim and glibenclamide, respectively). Data are provided as mean ± S.E.M. After the performance of the variance homogeneity test, a one-way and two-way analysis of variance was used. Fisher's exact test was performed in case of MES. P-value less than 0.05 considered statistically significant. Resultsand Discussion: Our data showed that IVM (0.5, 1, 5, and 10 mg/kg, i.p.) increased CST. Furthermore, flumazenil 0.25 mg/kg, i.p. and glibenclamide 1 mg/kg, i.p., could inhibit the anticonvulsant effects of IVM. Supplementary, an ineffective dose of diazepam 0.02 mg/kg, i.p. or cromakalim 10 μg/kg, i.p. were able to enhance the anticonvulsant effects of IVM. Besides, we figure out that the IVM (1 and 5 mg/kg, i.p.) could delay the onset of first clonic seizure and also might decrease the frequency of clonic seizures induced by PTZ (85 mg/kg, i.p.). Finally, IVM could prevent the incidence and death in MES-induced tonic-clonic seizures. ConclusionBased on the obtained results, it can be concluded that IVM may exert anticonvulsant effects against PTZ- and MES-induced seizures in mice that might be mediated by GABAA receptors and KATP channels.

Anti-seizure properties of Ipomoea asarifolia (Desr.) (Convolvulaceae) ethanolic leaf extract in laboratory animals

BackgroundPreparation of Ipomoea asarifolia (Desr.) (Convolvulaceae) is widely used in traditional African medicine for the treatment of different kinds of ailments such as syphilis, malaria, convulsions and rheumatism.AimThe present study examined the median lethal dose (LD50) and possible anti-seizure potentials of Ipomoea asarifolia ethanolic leaf extract using acute seizure models.ResultsThe intraperitoneal LD50 of Ipomoea asarifolia ethanolic leaf extract in mice and chicks was found to be 2,150 mg/kg. The Ipomoea asarifolia ethanolic leaf extract has shown significantly (p < 0.05) delayed time for the onset of seizure against pentylenetetrazole- and strychnine-induced seizures in a non-dose dependent manner both at 300 mg/kg. The extract has also shown significant (p < 0.01, p < 0.001 and p < 0.001) delayed time for onset of seizures against 4-aminopyridine-induced seizure model in a dose-dependent manner at doses of 150, 300 and 600 mg/kg respectively. The extract has not shown appreciable activity against picrotoxin and maximum electroshock-induced seizure models.ConclusionsThe present study revealed that Ipomoea asarifolia ethanolic leaf extract possesses anti-seizure properties which supports its folkloric use for the management of convulsions.

Neuropharmacological evaluation and HPTLC fingerprint profile of phytocompound-enriched chloroform fraction of methanolic extract of Lagenaria siceraria (Molina) Standley fruits - a potent Asian ethno-medicinal vegetable plant.

Lagenariasiceraria (Molina) Standley (Cucurbitaceae) is a traditional vegetable plant, popularly known as bottle gourd (English) and lauki (Hindi). It is a climbing herb characterized with a number of therapeutic properties. Traditionally Lagenariasiceraria (LS) fruits were used for their cardioprotective, hepatoprotective, diuretic, and purgative effects, but there is very little scientific data available on its neuroprotective potential.

Lamotrigine and retigabine increase motor threshold in transcranial magnetic stimulation at the dose required to produce an antiepileptic effect against maximal electroshock-induced seizure in rats

Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.

EVALUATION OF PHARMACOLOGICAL EFFECT OF CASSIA SOPHERA LINN LEAVES EXTRACTS

Instroduction: Cassia sophera Linn (C. sophera) is a medicinally important plant belonging to the family of Caesalpiniaceae. The whole part of the plant is used as traditional folk medicine and is reported to possess analgesic, anticonvulsant, antioxidant, anti-inflammatory, hepatoprotective and antiasthmatic activity.&#x0D; Materials and Methods: Eddy’s hot plate and Analgesiometer tests were used to asses the antinociceptive activity of Cassia sophera. Pentobarbitone narcosis potentiation test was used to evaluate the hypnotic and sedative effect, while anticonvulsant activity was evaluated by Maximum electroshock-induced seizure test and Pentylenetetrazol induced seizure test.&#x0D; Results and Discussion: Test drug (440 mg/kg) produced significant analgesia, potentiated the pentobarbitone induced sleeping time and exhibited anticonvulsant effect against hind limb tonic extension phase of maximum electroshock-induced seizure test and seizures induced by pentylenetetrazol.&#x0D; Conclusion: The preliminary screening of seed extract of Cassia sophera, Linn. exhibited analgesic, anticonvulsant effects and potentiated pentobarbitone sleeping time. The ethanol extract of seed of Cassia sophera, Linn. deserves further investigation to elucidate the mechanisms of action.

Anticonvulsant Activity of Helianthus tuberosus Against Maximal Electroshock Induced Convulsions in Rats

Epilepsy is an episodic brain dysfunction featured by recurring erratic spontaneous seizures followed by cognitive, social, neurobiological, and psychological consequences. Conventional anti-epileptic drugs are associated with several untoward effects, and hence long-term treatment compliance is a major problem in the management of epilepsy. Herbal drugs have shown promising efficacy as potent anticonvulsants in the past few years. In light of this, the anticonvulsant effect of alcoholic extract of leaves of Helianthus tuberosus (AHT) against maximal electroshock (MES) induced convulsions was investigated. In the present investigation, an indigenous plant, H. tuberosus was studied for its protective effect against maximal electroshock (MES) induced convulsions in Wistar albino rats. The rats were pre-treated with different doses (100, 200, 400 mg/kg) of alcoholic extract of leaves of H. tuberosus for 14 days, and then, they were subjected to maximal electroshock seizures (40 mA for 0.2 seconds) treatment. Alcoholic extract of leaves of H. tuberosus at the dose of 400 mg/kg significantly reduced the duration of hind limb extension and the protection of rats against maximal electroshock-induced seizures. The reference standards phenytoin (20 mg/kg) provided complete protection. Thus, the present study revealed an anticonvulsant effect of H. tuberosus against maximal electroshock-induced convulsions in rats.

Effect of acute and chronic exposure to lovastatin on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Numerous studies indicate neuroprotective activity of statins, commonly used cholesterol lowering drugs in epilepsy and several other neurological diseases. Promising anti-convulsant and neuroprotective effects of statins, attributed to their anti-excitotoxic and anti-inflammatory action were reported in several animals’ seizure models.To determine the effects of acute (single) and chronic (once daily for 7 consecutive days) administration of lovastatin on the protective activity of four classical antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock seizure model.Seizure activity (maximal electroconvulsions) in mice were generated by alternating current delivered via ear-clip electrodes. Adverse-effect profile of lovastatin combinations with the tested antiepileptic drugs was assessed in the chimney test (motor performance). Total brain concentrations of antiepileptic drugs were evaluated with the fluorescence polarization immunoassay technique as a measure of the pharmacokinetic interaction between drugs.Lovastatin administered acutely or chronically (5–20 mg/kg) did not significantly affect the threshold for electroconvulsions in mice. Acute lovastatin (10 mg/kg) significantly enhanced the anticonvulsant effect of valproate, which was accompanied with a 34% significant increase in total brain concentration of valproate. Acute lovastatin in combination with phenytoin impaired motor performance by notably decreasing the TD50 value of phenytoin. Chronic lovastatin (10 mg/kg) markedly enhanced the anticonvulsant potential of phenytoin.Acute lovastatin increased anticonvulsant action of valproate but also significantly raised level of valproate in brain after combined administration suggesting pharmacokinetic nature of interaction. The combinations of chronic lovastatin combined with phenytoin can potentially enhance the anticonvulsant potency of phenytoin.

Evaluation of Anticonvulsant Activity of 80% Methanolic Root Bark Extract and Solvent Fractions of Pentas schimperiana (A. Rich.) Vatke (Rubiaceae) in Swiss Albino Mice.

Background Epilepsy is one of the most common serious neurological disorders, responsible for substantial morbidity and mortality due to limited efficacy and negative properties of antiepileptic drugs. Medicinal plants are believed to be an important source of new chemical substances with potential therapeutic effects. Pentas schimperiana (A. Rich.) Vatke is a medicinal plant used in Ethiopian traditional medicine for the treatment of epilepsy. However, it lacks scientific investigation on its anticonvulsant activity. Therefore, this study was conducted to evaluate the anticonvulsant activity of 80% methanol root bark extract and solvent fractions of Pentas schimperiana (A. Rich.) Vatke in mice. Methods Anticonvulsant activity was evaluated by using the pentylenetetrazole and maximal electroshock-induced seizure test. The 80% methanolic root bark extract was subjected to successive fractionation with solvents differing polarity, i.e., chloroform, butanol, and water. The test groups received 100, 200, and 400 mg/kg bodyweight of extract and its solvent fractions. Result The ME400 and BF400 at the higher dose exhibited a significant (p < 0.001) anticonvulsant effect in both the pentylenetetrazole and maximal electroshock-induced seizure test compared with control. However, chloroform fraction only showed a significant (p < 0.001) anticonvulsant effect in the PTZ-induced seizure test, while aqueous fraction had least anticonvulsant activity in both seizure-induced tests. Phytochemical screening of Pentas schimperiana (A. Rich.) Vatke root bark extract revealed the presence of alkaloids, saponins, flavonoids, phenols, steroids, terpenoids, and tannins. Conclusion This study indicated that the plant has anticonvulsant activity and is considered as a potential source to develop a new antiepileptic drug.

Interactions among Lacosamide and Second-Generation Antiepileptic Drugs in the Tonic-Clonic Seizure Model in Mice.

Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.

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.

Anticonvulsive profile of two GABAB receptor antagonists on acute seizure mice models

IntroductionDL-3-hydroxy-3-phenylpentanamide (HEPP) and DL-3-hydroxy-3-(4′chlorophenyl)-pentanamide (Cl-HEPP) are phenyl-alcohol-amides that are metabotropic GABAB receptor (MGBR) antagonists and protective against absence seizures. This study aims to further characterize the anticonvulsant profile of these drugs. MethodsHEPP and Cl-HEPP were evaluated in various standardized acute seizure and toxic tests in female Swiss-OF1 mice. ResultsToxicities of HEPP and Cl-HEPP were limited; doses up to 30 mg/kg did not result in hypothermia, reduced spontaneous locomotor activity, or failure of the rotarod test, with doses >15 mg/kg potentiating pentobarbital-induced sleep. In maximal electroshock-induced seizures, 20 mg/kg Cl-HEPP protected 100 % of mice; lower doses shortened post-ictal recovery. Seizure protection occurred against subcutaneous pentylenetetrazole and picrotoxin, being limited against N-methyl-d-aspartate. In bicuculline test, clonic or fatal tonic seizures were decreased, onset delayed, and recovery improved; ED50 values (dose protecting 50 % of the animals) were 37.5 and 25 mg/kg for HEPP and Cl-HEPP, respectively. In magnesium deficiency-dependent audiogenic seizures (MDDAS), ED50 values were 3 and 8 mg/kg for Cl-HEPP and HEPP, respectively. The components of MDDAS (latency, wild running, seizure, and recovery phases) in unprotected animals were only minimally affected by near ED50 doses of Cl-HEPP and HEPP. DiscussionHEPP and, to a greater extent, Cl-HEPP provide anti-seizure protections in several acute seizure tests in mice at nontoxic doses. These results are consistent with the action of these drugs on diverse molecular targets directly resulting from their MGBR antagonistic properties. However, other mechanisms might occur possibly for the protection given in the MES test. Finally, a similarity in the modulation of MDDAS components between the two phenyl alcohol amides and ethosuximide could also be based on the MGBR antagonistic properties of the former, given the recently re-evaluated therapeutic relevant targets of the latter.

Effect of Chronic Administration of 5-(3-chlorophenyl)-4-Hexyl-2,4 -Dihydro-3H-1,2,4-Triazole-3-Thione (TP-315)-A New Anticonvulsant Drug Candidate-On Living Organisms.

About 70 million people suffer from epilepsy—a chronic neurodegenerative disease. In most cases, the cause of the disease is unknown, but epilepsy can also develop as the result of a stroke, trauma to the brain, or the use of psychotropic substances. The treatment of epilepsy is mainly based on the administration of anticonvulsants, which the patient must most often use throughout their life. Despite significant progress in research on antiepileptic drugs, about 30% of patients still have drug-resistant epilepsy, which is insensitive to pharmacotherapy used so far. In our recent studies, we have shown that 4-alkyl-5-aryl-1,2,4-triazole-3-thiones act on the voltage-gated sodium channels and exhibit anticonvulsant activity in an MES (maximal electroshock-induced seizure) and 6Hz test in mice. Previous studies have shown their beneficial toxic and pharmacological profile, but their effect on a living organism during chronic use is still unknown. In the presented study, on the basis of the previously conducted tests and the PAMPA (parallel artificial membrane permeability assay) BBB (blood–brain barrier) test, we selected one 1,2,4-triazole-3-thione derivative—TP-315—for further studies aimed at assessing the impact of its chronic use on a living organism. After long-term administration of TP-315 to Albino Swiss mice, its effect on the functional parameters of internal organs was assessed by performing biochemical, morphological, and histopathological examinations. It was also determined whether the tested compound inhibits selected isoforms of the CYP450 enzyme system. On the basis of the conducted tests, it was found that TP-315 does not show nephrotoxic nor hepatotoxic effects and does not cause changes in hematological parameters. In vitro tests showed that TP-315 did not inhibit CYP2B6, CYP2D6, CYP3A4, or CYP3A5 enzymes at the concentration found in the serum of mice subjected to long-term exposure to this compound.

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 &amp; 4 received Nebivolol 0.25 mg/kg oral &amp; 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&lt;0.01) and clonus (p&lt;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.

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity.

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano‐vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification–solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl‐lactic‐co‐glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP‐PLGA‐NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP‐PLGA‐NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma‐aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme‐linked immunosorbent assay. The maximal electroshock‐induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP‐loaded NPs. The prepared ZP‐PLGA NPs were negatively charged spherical particles with an average size of 120–300 nm. Optimized ZP‐PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42‐fold augmentation in oral drug bioavailability in comparison to ZP‐marketed products. Moreover, parenteral administration of ZP‐NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP‐PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.