Maximal Electroshock Test Research Articles

Structure-activity relationship study on new hemorphin-4 analogues containing steric restricted amino acids moiety for evaluation of their anticonvulsant activity.

In the present study, several new analogues of hemorphin-4, modified with unnatural conformationally restricted amino acids followed the structure Aaa-Tyr-Xxx-Trp-Thr-NH2, where Aaa is the low-molecular-weight lipophilic adamantyl building block, and Xxx is Ac5c (1-aminocyclopentanecarboxylic acid) or Ac6c (1-aminocyclohexane carboxylic acid) was synthesized, characterized and investigated for anticonvulsant activity in three seizure tests, the maximal electroshock test (MES), 6-Hz psychomotor seizure test and timed intravenous pentylenetetrazole infusion (ivPTZ) test. The acute neurological toxicity was determined using the rota-rod test. The new synthetic neuropeptide analogues were prepared by solid-phase peptide synthesis-Fmoc chemistry and were evaluated in three doses of 1, 3 and 5µg, respectively, administered intracerebroventricularly in male ICR mice. The physicochemical properties of these peptide analogues were evaluated as pKa and pI values were calculated using potentiometry. The IR spectrum of the compounds was recorded and the characteristic lines of both adamantane moiety and the peptide backbone were registered in the wavelength range from 4000 to 400cm-1. The hexapeptide Ang IV was used as a positive control. From the six synthesized peptide analogues, the P4-5 was the most active at doses of 1 and 3µg in the three seizure tests. The order of potency of other peptides was as follows: P4 > P4-3 = P4-4 > P4-2 > Ang IV in MES, P4-4 ≥ P4-1 > P4-3 > P4-2 > P4 > Ang IV in 6-Hz test and P4-4 = P4-3 > P4-2 = P4 > Ang IV in ivPTZ test. None of the peptides displayed neurotoxicity in the rota-rod test. Docking study results suggest that direct H-bonding and ionic interactions between our synthetic ligands and residues, responsible for coordination of Zn2+ along with hydrophobic interactions between our ligands and IRAP active site are the most important for the ligand binding. The results propose that incorporation of adamantane and cycloalkane building blocks in the peptide chain of the hemorphin-4 scaffold is important for the potential high biological activity.

Assessment of Neuropharmacological Profile of Ethanolic Extract of Lawsonia Inermis Flowers

On preliminary basis neuropharmacological profile of ethanolic extract of flowers of Lawsonia inermis was carried out. For assessing the activity of flowers on central nervous system locomotor activity using actophotometer, muscle relaxant activity using rotarod apparatus, pentobarbital-induced hypnosis and anticonvulsant activity by maximal electroshock test was performed. Ethanolic extract of flowers of Lawsonia inermis decreased the motor activity by 48.63 % and showed 49.03% noteworthy muscle relaxation along with 127.73% potentiation of pentobarbital-induced sleeping time and 66.67% decreased the duration of tonic hind leg extension of seizures activity. The results conclude that the extract of flowers of Lawsonia inermis has significant central nervous system depressant activity. Further investigations are, however, necessary to explore mechanism(s) of action involved in these pharmacological activities.

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.
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Evaluation of the Possible Anticonvulsant Effect of Δ9-Tetrahydrocannabinolic Acid in Murine Seizure Models.

Introduction: The cannabinoid Δ9-tetrahydrocannabinolic acid (Δ9-THCA) has long been suggested in review articles and anecdotal reports to be anticonvulsant; yet, there is scant evidence supporting this notion. The objective of this study was to interrogate the anticonvulsant potential of Δ9-THCA in various seizure models—the Scn1a+/− mouse model of Dravet syndrome, the 6-Hz model of psychomotor seizures and the maximal electroshock (MES) model of generalized tonic-clonic seizures.Materials and Methods: We examined the effect of acute Δ9-THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in the Scn1a+/− mice. We also studied the effect of acute Δ9-THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Δ9-THCA was used in the studies or a mixture of Δ9-THCA and Δ9-THC.Results: We observed mixed anticonvulsant and proconvulsant effects of Δ9-THCA across the seizure models. Highly pure Δ9-THCA did not affect hyperthermia-induced seizures in Scn1a+/− mice. A Δ9-THCA/Δ9-THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Δ9-THCA and Δ9-THC had no effect. Conversely, both Δ9-THCA and Δ9-THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Δ9-THCA/Δ9-THC mixture. The Δ9-THCA/Δ9-THC mixture, however, increased spontaneous seizure severity and increased mortality of Scn1a+/− mice.Discussion: The anticonvulsant profile of Δ9-THCA was variable depending on the seizure model used and presence of Δ9-THC. Because of the unstable nature of Δ9-THCA, further exploration of Δ9-THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Δ9-THCA and Δ9-THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.

Design, synthesis, and pharmacological evaluation of novel 1,2,4-triazol-3-amine derivatives as potential agonists of GABAA subtype receptors with anticonvulsant and hypnotic effects

In the current study, a series of novel 1,2,4-triazol-3-amine derivatives were designed, synthesized, and biologically evaluated in vivo for their anticonvulsant and hypnotic effects in the pentylenetetrazole (PTZ)-induced seizures, maximal electroshock (MES)-induced seizures, and pentobarbital-induced sleeping tests. Furthermore, the possible side effects of the most potent compounds on the memory, motor coordination, and muscle strength were evaluated in passive avoidance, rotarod, and grip strength tests, respectively. The designed compounds with the main benzodiazepine pharmacophores including aromatic ring and proton accepting group completely mimiced the structure of zolpidem as an α1-selective agonist of GABAA receptor. Compounds 5c (ED50 ≈ 52.5 mg/kg) and 5 g (ED50 ≈ 16.5 mg/kg) in the PTZ test were the most potent compounds among the designed compounds. In the MES test, the observed ED50s for compounds 5c and 5 g were reduced to around 11.8 mg/kg and 10.5 mg/kg, respectively. The considerable hypnotic effect in a dose-dependent manner was observed following the administration of newly synthesized compounds. In all experiments administration of flumazenil as an antagonist of benzodiazepines receptor fully antagonized observed effects which indicated the involvement of GABAA receptors. Since there was no negative effect on memory, motor coordination, and muscle strength following the administration of compounds 5c and 5g as the most potent compounds, it could be concluded that the novel compounds most likely act through α1-containing GABAA receptors and possess no affinity for α5-containing receptors. The newly designed compounds could be considered as leading compounds in synthesizing novel GABAA receptor agonists with minimum side effects.

Synthesis, Anticonvulsant and Antinociceptive Activity of New Hybrid Compounds: Derivatives of 3-(3-Methylthiophen-2-yl)-pyrrolidine-2,5-dione.

The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.

Anti-epileptic potentials of the partitioned fractions of chamaecrista mimosoides

This research work aimed to establish scientific basis for the use of Chamaecrista mimosoides, in traditional medicine as anti-epileptic medication. The whole plant part of Chamaecrista mimosoides was extracted with ethanol and screened for phytochemicals. Acute toxicity study was carried out using Lorke’s method and the antiepileptic activity was evaluated using maximal electroshock induced seizure test in day-old chicks, pentylenetetrazole (PTZ) and strychnine using mice. The phytochemical study revealed the presence of saponins, cardiac glycosides, tannins, flavonoids, terpenoids and cardenolides. Both the chloroform, ethylacetate and n-butanol portions at 100, 250, and 500mg/kg body weight did not protect the chicks against tonic hind limb extension (THLE) in maximal electro-shock test (MEST). The chloroform and n-butanol portions at doses of 250 and 500 mg/kg body weight protected 40% and 60% of mice against clonic spasm induced by pentylenetetrazole, while ethyl-acetate soluble portion did not protect the mice against clonic spasm induced by pentylenetetrazole at all doses used when compared to Valproic acid (200 mg/kg) protected all the mice (100%) against clonic spasm induced by pentylenetetrazole. The chloroform soluble portion at the doses of 100, 250 and 500 mg/kg body weight protected 40%, 100%, 100% against death induced by strychnine, while ethylacetate and n-butanol portions did not protect the rats against death induced by strychnine but prolonged the onset of convulsion. In all the tests, phenobarbitone (20 mg/kg) was used as positive control and protected 80% of mice against convulsion induced by strychnine. The antiepileptic investigation suggests that the chloroform portion of Chamaecrista mimosoides has a promising antiepileptic activity. Â

Novel 3-Substituted-2, 3-Dihydro-2-Thioxoquinazolin-4-(1H)-one derivative as Anticonvulsants: Synthesis, Molecular Docking and Pharmacological Screening

Background: According to the World Health Organization, 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. 2,3 disubstituted quinazolinone-4-one derivatives endowed with various pharmacological activity, particularly having anticonvulsant action. Objectives: The aim of this study was to synthesize 3-Substituted-2,3-Dihydro-2-thioxoquinazolin- 4-(1H)-one derivative and evaluate for anticonvulsant activity and neurotoxicity in order to find an efficient, compound with lesser side effects. Methods: A novel series of 3-[4-(2-amino-5, 6-dihydro-4(substituted phenyl)-4H-1, 3-oxazin /thiazin-6yl) phenyl]-2, 3-dihyro-2-thioxoquinazolin-4(1H)-one derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were assigned on the basis of spectral data (UV, IR, 1HNMR, 13CNMR and MS) and performed anticonvulsant activity against maximal electroshock test and Subcutaneous Pentylenetetrazole model. Neurotoxicity was assessed using a rotarod apparatus test. The molecular docking study was performed to assess their binding affinities towards Gamma-Aminobutyric Acid type A receptor. A quantitative estimate of drug-likeness was also performed, which calculates the molecular properties and screen the molecules based on drug-likeness rules. Results: Compounds 4b, 4e, 4j and 4m have shown the highest anticonvulsant activity against tonic seizure with decreased mean duration of tonic hind leg extension of 8.31, 7.35, 8.61 and 8.99 s, respectively in maximal electroshock model and increased onset time clonic convulsion duration of 94.45, 96.65, 93.51 and 91.86 s in Subcutaneous Pentylenetetrazole model. Molecular docking study revealed a better binding affinity with Gamma-Aminobutyric Acid type A receptor. Conclusion: The compound 4b and 4e emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity. The obtained results showed that compounds 4b and 4e could be useful as a template for future design, optimization, and investigation to produce more active analogs.

Design, synthesis and anticonvulsant activity of new imidazolidindione and imidazole derivatives

New imidazolidindiones and tetra-substituted imidazole derivatives were designed, synthesized, and evaluated for the anticonvulsant activity through pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) tests using valproate sodium and phenytoin sodium as reference drugs, respectively. Most of the target compounds showed excellent activity against pentylenetetrazole (PTZ)-induced seizures with fair to no-activity against MES. Compounds 3d, 4e, 11b, and 11e showed higher activity (120%) than that of valproate sodium in PTZ model. Almost all compounds showed no neurotoxicity, as indicated by the rotarod test. Estimation of physicochemical properties and pharmacokinetic profiles of the target compounds were studied. The chemical structures of the target compounds were characterized by different spectrometric methods and elemental analysis.

Multitargeted Compounds Derived from (2,5-Dioxopyrrolidin-1-yl)(phenyl)-Acetamides as Candidates for Effective Anticonvulsant and Antinociceptive Agents.

We developed a focused set of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant and antinociceptive properties. These hybrid compounds demonstrated broad-spectrum protective activity in a range of mouse models, such as the maximal electroshock (MES) test, the pentylenetetrazole-induced seizures (scPTZ), and the 6 Hz (32 mA) seizures. Compound 22 showed the most potent anticonvulsant activity (ED50 MES = 23.7 mg/kg, ED50 6 Hz (32 mA) = 22.4 mg/kg, ED50scPTZ = 59.4 mg/kg). In addition, 22 revealed potent efficacy in the formalin-induced tonic pain. These in vivo activities of 22 are likely mediated by several targets and may result from the inhibition of central sodium/calcium currents and transient receptor potential vanilloid 1 (TRPV1) receptor antagonism. Finally, the lead compound 22 revealed drug-like absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) properties in the in vitro assays, making it a potential candidate for further development in epilepsy and neuropathic pain indications.

Phytochemical and Anti-epileptic Studies of Ethanol Extract of Boswellia dalzielii (Frankincense Tree) Stem Bark

Aim: This research work aimed to establish scientific basis for the use of Boswellia dalzielli stem bark, in traditional medicine as anti-epileptic medication.
 Methodology: The fresh stem bark of Boswellia dalzielii was extracted using absolute ethanol and screened for phytochemicals. Acute toxicity study was carried out using Lorke’s method and the antiepileptic activity was evaluated using maximal electroshock induced seizure test in day-old broiler chicks and pentylenetetrazole (PTZ) using Wistar strain mice.
 Results: Phytochemical screening of ethanol extract of B. dalzielii stem bark revealed that the presence of saponins, tannins, flavonoids and steroids/terpenoides. The intrapertoneal median lethal dose value (LD50) of BDE in mice was 2592.3 mg/kg, indicating the stem bark extract is relatively safe. The extract at the dose of 500 mg/kg body weight protected 40% of animals against PTZ-induced convulsion and also protected 20% of chicks against Tonic Hindlimb Extension (THLE) phase of the Maximal Electroshock Test (MEST) significantly (p<0.05).
 Conclusion: The antiepileptic investigation suggests that ethanol extract of B. dalzielii stem bark has antiepileptic activity.

Screening of Some Novel 4, 5 Disubstituted 1, 2, 4-Triazole-3-thiones for Anticonvulsant Activity.

In the present study, we synthesized fifteen 4, 5-disubstituted 1, 2, 4-triazol- 3-thione derivatives and evaluated for anticonvulsant activity with neurotoxicity determination. The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The molecular docking study was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. The anticonvulsant activity was assessed by maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) tests. The neurotoxicity was assessed by rotarod ataxia test. In MES test, compounds 5a, 8a and 9a were found active at 100 mg/kg and five compounds were found active at 300 mg/kg dose after 1 hr of administration. After 4 hr of drug administration, only two compounds 8a and 9a exhibited protection at 100 mg/kg. In scPTZ test, three compounds 2a, 6a and 8a were found active at 100 mg/kg and 7a was active at 300 mg/kg after 1 hr of test drug administration. Most of the compounds were found active in MES test with 8a and 9a being the most active among all. In docking study, 2a was found to be best compound based on the binding energy of -6.5 kcal/mol and estimated inhibition constant of 17.2 µM. Majority of synthesized compounds were found active in MES test, whereas only few were found to possess anti scPTZ activity. Among all compounds, only 14a caused motor coordination impairment in rotarod ataxia test at 300 mg/kg 1 hr duration.

Synthesis of Dibenzofuranone-Oxime Derivatives with Anticonvulsant, Antihypoxic, and Anti-Ischemic Activity

New dibenzofuranone-oxime derivatives were designed based on active structures of oxime esters. Compounds of the proposed group were synthesized using 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and aromatic acid chlorides. The anticonvulsant activity of the new compounds was studied. The structure— activity relationship was analyzed. Compound 1a [3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(3,4-dichlorobenzoyl)oxime] was the most active compound after i.p. injection to mice in the maximal electroshock test over a wide dose range of 20 – 100 mg/kg. Compound 1a at doses of 10 and 30 mg/kg exhibited antihypoxic activity in a hypoxia test with hypercapnia in a hermetic chamber and anti-ischemic activity at a dose of 10 mg/kg in a rat ischemic stroke model.

Anticonvulsant Effect of Alcea aucheri on Pentylenetetrazole and Maximal Electroshock Seizures in Mice.

Introduction:This study was designed to investigate the possible anticonvulsant effect of acute administration of an aqueous extract of flowers of Alcea aucheri (EFA) in two in vivo seizure models.Methods:Seizures were induced in male adult Swiss mice by administration of Pentylenetetrazol (PTZ) or Maximal Electroshock (MES). Mice were randomly subjected to receive saline, EFA (8.75–175 mg.kg−1), or diazepam intraperitoneally (i.p.) 15 or 30 min before PTZ injection. In another experiment, mice were treated (i.p.) with saline, EFA (8.75–350 mg.kg−1), or phenytoin 15 or 30 min before the MES test. Diazepam and phenytoin were used as reference drugs.Results:EFA (175 mg.kg−1) significantly increased the PTZ-induced seizure threshold compared with the saline control group 15 min after its administration. In the MES test, the extract (35 mg.kg−1) increased the latency to onset of tonic Hind Limb Extension (HLE) (seizure activity) compared with the saline group 15 min after treatment. Also, 30 min after treatment, EFA (35, 70, and 175 mg.kg−1) increased the latency to onset of the seizure, decreased the duration of the seizure (70 mg.kg−1), and decreased seizure occurrence (350 mg.kg−1) compared with those of the saline group. At both time points, the extract at all doses significantly reduced the mortality rate compared with the saline group.Conclusion:These findings provide evidence of a possible anticonvulsant effect of A. aucheri in PTZ and MES seizure models in mice.

Nebivolol attenuates the anticonvulsant action of carbamazepine and phenobarbital against the maximal electroshock-induced seizures in mice

BackgroundDue to co-occurrence of seizures and cardiovascular disorders, nebivolol, a widely used selective β1-blocker with vasodilatory properties, may be co-administered with antiepileptic drugs. Therefore, we wanted to assess interactions between nebivolol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital in the screening model of tonic–clonic convulsions.MethodsSeizure experiments were conducted in the electroconvulsive threshold and maximal electroshock tests in mice. The chimney test served as a method of assessing motor coordination, whereas long-term memory was evaluated in the computerized step-through passive-avoidance task. To exclude or confirm pharmacokinetic interactions, we measured brain concentrations of antiepileptic drugs using the fluorescence polarization immunoassay.ResultsIt was shown that nebivolol applied at doses 0.5–15 mg/kg did not raise the threshold for electroconvulsions. However, nebivolol at the dose of 15 mg/kg reduced the anti-electroshock properties of carbamazepine. The effect of valproate, phenytoin, and phenobarbital remained unchanged by combination with the β-blocker. Nebivolol significantly decreased the brain concentration of valproate, but did not affect concentrations of remaining antiepileptic drugs. Therefore, contribution of pharmacokinetic interactions to the final effect of the nebivolol/carbamazepine combination seems not probable. Nebivolol alone and in combinations with antiepileptic drugs did not impair motor performance in mice. Nebivolol alone did not affect long-term memory of animals, and did not potentiate memory impairment induced by valproate and carbamazepine.ConclusionsThis study indicates that nebivolol attenuated effectiveness of some antiepileptic drugs. In case the results are confirmed in clinical settings, this β-blocker should be used with caution in epileptic patients.

Anticonvulsant studies on the isolated compounds from the leaves of Scurrula parasitica L (Loranthaceae)

The leaves of Scurrula parasitica were effectively extracted by means of cold extraction method. Fractionation and purification of the n -hexane, ethyl acetate and methanol crude extracts yielded eight compounds. The compounds were identified as quercetin 1 , quercitrin 2 , kaempferol 3- O -a-L-rhamnoside 3 , (+)-catechin 4 , lupeol 5 , lupeol palmitate 6 , b-sitosterol 7 and squalene 8 . Compounds 1 , 4 , 5 and 6 were investigated for anticonvulsant potentials using maximal electroshock test in chicks and pentylenetetrazole-induced seizure test in mice while the effect of the compounds on motor coordination was investigated using beam walking assay in mice. The compounds did not completely protect the mice against pentylenetetrazole-induced seizure, but increased the mean onset of myoclonic jerks and spasms in the animals. Quercetin significantly ( p < 0.05) increased the mean onset of spasm in the unprotected animals. The compounds also differentially protected the mice against mortality. Conversely, the compounds did not protect the chick against the MEST. Similarly, they did not significantly reduce the recovery time. In the beam walking assay, the increase in the number of foot slips observed in the study may be associated with the interaction of quercetin and (+)-catechin with the GABA system to produce clinical sedation. The findings of the present study suggest that the isolated compounds possess some mild anticonvulsant potential and may be beneficial in the management of petit mal epilepsy.

Design, Synthesis and Biological Evaluation of Benzo[D]Thiazole with Dimethylpyrazol Derivatives.

A series of new benzothiazole derivatives containing dimethylpyrazole were synthesized and evaluated for their anticonvulsant activity, neurotoxicity and cytotoxicity by using the maximal electroshock (MES), rotarod neurotoxicity (TOX) and MTT colorimetric assay. Among the compounds studied, four compounds (6a, 6b, 6g and 6m) showed better anticonvulsant than the others at 300 mg/kg and they also showed anticonvulsant activity at the dose of 100 mg/kg. All the synthetic compounds showed lower neurotoxicity and little cytotoxicity, so that the compounds, which with better activities, also had higher protective index. In particular, the compound 6g, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-((2-fluorobenzyl)oxy)benzo[d]thiazole showed better activity with an ED50 value of 160.4 mg/kg and higher protective index (PI) values of 2.74 in the MES test than the standard drugs sodium valproate, which used as positive controls in this study. After that the compound 6g demonstrated antagonistic activity against seizures induced by pentylenetetrazol, which proved 6g maybe exert activity through effecting GABAergic neurotransmission.

Design, Synthesis and Biological Activity of Some 4, 5-Disubstituted-2, 4- Dihydro-3H-1, 2, 4- Triazole-3-Thione Derivatives.

In the present study, 4, 5-disubstituted triazol-3-thione derivatives were synthesized and evaluated for anticonvulsant activity along with neurotoxicity determination. The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The anticonvulsant activity was assessed by Maximal Electroshock (MES) test and subcutaneous Pentylenetetrazole (scPTZ) tests and neurotoxicity was assessed by rotarod test. Docking was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. The compounds 7a and 9a with significant pharmacological activity were also found to interact with LYS329 residue of GABA-AT by H-bond with a docking score of -5.92 kcal/mol (Ki = 41.99 μM) and -5.87 kcal/mol (Ki = 49.83 μM) respectively. Most of the compounds were found to be active in MES test but only seven showed protection in scPTZ test.

Discovery of [1,2,4]-triazolo [1,5-a]pyrimidine-7(4H)-one derivatives as positive modulators of GABAA1 receptor with potent anticonvulsant activity and low toxicity

In searching for more effective and safer antiepileptic drugs, a series of 2,5-disubstituted [1,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one derivatives were designed and synthesized. Spontaneous Ca2+ oscillations (SCOs) of cortical neurons were used for in vitro phenotypic screening. Maximal electroshock test (MES) and pentylenetetrazole (PTZ) test were used to access their anticonvulsant activity, and rotarod test was used to estimate their neurotoxicity. The active compounds in in vitro model are specifically effective in pentylenetetrazole (PTZ)-induced epilepsy model but not maximal electroshock (MES) model, more importantly with lower neurotoxicity as compared to commonly used drugs. Among them, compound 5c and 5e showed significant anticonvulsant activities in PTZ-induced epilepsy model with ED50 values at 31.81 mg/kg and 40.95 mg/kg, respectively. These compounds have improved neurotoxicity with protective index (PI = TD50/ED50) values at 17.22 and 9.09, respectively. Finally we demonstrated that compound 5c and 5e mainly acted on GABAA receptor as positive modulators but not sodium channels. Thus the present study has provided potential candidates for further investigation in epilepsy.

Neuropharmacological activities of ethanol leaf extract of &lt;i&gt;Cussonia barteri&lt;/i&gt; Seeman (Araliaceae) in laboratory animals

The anticonvulsant studies on Cussonia barteri Seeman (Araliaceae) were carried out using maximal electroshock test (MEST), pentylenetetrazole and strychnine-induced seizures model in chicks and mice. In addition, sedative and anxiolytic effect of the extract was evaluated using diazepam-induced sleeping time, hole-board, beam walk assay and open field test in mice. The extract was also evaluated for acute toxicity. The oral and intraperitoneal LD50 of the extract was estimated to be greater than 5,000 mg/kg and 2, 154.1 mg/kg body weight respectively. The extract did not protect the chicks against maximal electroshock seizure; neither did it shorten the mean recovery time. The extract produced 66.67% and 83.33% protection against strychnine and pentylenetetrazole induced seizures respectively at the highest dose (400 mg/kg) tested. The extract decreases the number of head dips in hole-board test, suggesting its sedative property, which was confirmed by the ability of extract to prolonged diazepam sleeping time. The extract did not significantly increase the time spent on the beam but at the highest dose tested significantly increased the number of foot slips, an index of motor coordination deficit. The extract insignificantly decreased number of rearing, Total Square and Central Square crossed in an open field test. These results suggest that the extract may contain compound(s) that may be beneficial in the management of absence or myoclonic seizures.Keywords: Cussonia barteri; Epilepsy; Seizure; Sedative; Anxiolytic