Strychnine-induced Seizures Research Articles

Anticonvulsant activity of Tetrahydrolinalool: behavioral, electrophysiological, and molecular docking approaches.

Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.

Exploring the Antiepileptic Potential of Amaranthus spinosus: An Experimental Study in Albino Mice

About 60% of the world population relies on herbal medicine, and 80% depend almost entirely on it for their primary healthcare. Many of these herbs are rich in phytochemicals, thus valuable as potential sources of drugs. Amaranthus spinosus is a vegetable and ornamental plant used in African folklore to treat several illnesses. This study aimed to investigate the antiepileptic potential of the methanol leaf extract of Amaranthus spinosus in albino mice. Preliminary phytochemical screening and acute toxicity studies were conducted using standard methods. Anticonvulsant studies were conducted using chemo-shock models (pentylenetetrazole (PTZ) - and strychnine (STR)-induced seizures) in mice. Phytochemical screening has revealed the presence of terpenoids, tannins, saponins, alkaloids, anthraquinones, carbohydrates, cardiac glycosides, and flavonoids. Additionally, the acute toxicity studies of the extract revealed that the extract is safe in mice at 2000 mg/kg. The extract at 400 and 800 mg/kg produced a significant (p<0.05) delay in the mean onset of seizures, decreased the duration of seizures induced by PTZ in a dose-dependent manner, and protected the mice. The extract showed insignificant protection against strychnine-induced seizures in mice. This could serve as a scientific basis for further evaluation of the plant’s potential in managing epilepsy, which can lead to the discovery of an effective antiepileptic agent with fewer side effects.

Evaluation of anticonvulsant activity of methanol leaf extract of Opilia celtidifolia diels (opiliaceae) in mice and chicks

Epilepsy affects 1% of the global population, with around 2.4 million new diagnoses annually. Approximately 80% of individuals with epilepsy reside in low- and middle-income countries, with a prevalence of 8.2 per 1000 in sub-Saharan Africa and 8 per 1000 in Nigeria. This study evaluated the anticonvulsant properties of methanol leaf extract of Opilia celtidifolia (MEC) in mice and chicks. The median lethal dose (LD50) of the extract was determined in mice and chicks. The acute anticonvulsant properties of MEC were evaluated using pentylene tetrazole (PTZ), maximal electroshock (MES), strychnine, and picrotoxin-induced convulsions, while the chronic anticonvulsant effect was assessed through PTZ-induced kindling. The effects of MEC on cognition, coordination, motor deficits, sedation, and locomotion were assessed using the Y Maze, Beam Walking, and Open Field tests. The extract increased the mean percentage of survival and significantly delayed the mean onset of PTZ-induced seizure (p<0.05), strychnine-induced seizure (p<0.01), and picrotoxin-induced seizures (p<0.05) at a dose of 1000 mg/kg. However, the extract did not provide protection against MES-induced seizures. In the kindling model, the extract-treated mice exhibited a decrease in the seizure threshold, with an associated increase in oxidative stress. The extract treated mice showed significant (p<0.05) decrease in locomotor activity with apparent sedative effect but there was no obvious cognitive impairment in learning and memory, coordination or motor deficits. MEC is apparently non-toxic and possesses anticonvulsant activity against some animal models of epilepsy. It also exhibited decreased locomotor activity with apparent sedative effect in mice.

Anti-Strychnine Immunoconjugate Reduces the Effects of Strychnine-Induced Toxicity in Mice.

Strychnine poisoning induces seizures that result in loss of control of airway muscles, leading to asphyxiation and subsequent death. Current treatment options are limited, requiring hands-on medical care and isolation to low-stimulus environments. Anticonvulsants and muscle relaxants have shown limited success in cases of severe toxicity. Furthermore, nonfatal strychnine poisoning is likely to result in long-term muscular and cognitive damage. Due to its potency, accessibility, and lack of effective antidotes, strychnine poses a unique threat for mass casualty incidents. As a first step toward developing an anti-strychnine immunotherapy to reduce or prevent strychnine-induced seizures, a strychnine vaccine was synthesized using subunit keyhole limpet hemocyanin. Mice were vaccinated with the strychnine immunoconjugate and then given a 0.75 mg/kg IP challenge of strychnine and observed for seizures for 30 min. Vaccination reduced strychnine-induced events, and serum strychnine levels were increased while brain strychnine levels were decreased in vaccinated animals compared to the control. These data demonstrate that strychnine-specific antibodies can block the seizure-inducing effects of strychnine and could be used to develop a therapeutic for strychnine poisoning.

Neuropharmacology Potential of the Hydroalcoholic Extract from the Leaves of Piper cernuum: Anxiolytic, Hypnotic, and Antidepressant-Like Effects.

The use of medicinal plants in the treatment of mental illnesses is a reality that accompanies the history of civilizations, and the Piper genus exhibits many species with pharmacologically proven central effects. Then, this study evaluated the neuropharmacological effects of the hydroalcoholic extract from Piper cernuum (HEPC) leaves to validate its uses in folk medicine. Primarily Swiss mice (female, 25-30 g) were pretreated with HEPC (50-150 mg/kg, p.o.), vehicle, or the positive control, and submitted to open-field test (OFT), inhibitory avoidance test (IAT), tail suspension test (TST), and forced swim test (FST). Also, mice were exposed to pentylenetetrazol- and strychnine-induced seizure assay, pentobarbital-induced hypnosis test, and elevated plus-maze (EPM). The GABA levels and MAO-A activity were measured in the animal's brain after 15 days of HEPC administration (150 mg/kg, p.o.). Mice pretreated with HEPC (100 and 150 mg/kg) and exposed to pentobarbital presented decreased sleep latency and increased sleep duration (HEPC 150 mg/kg). In EPM, the HEPC (150 mg/kg) increased the frequency of entry and the time of exploration of mice in the open arms. The antidepressant-like properties of HEPC were demonstrated by the decrease in the mice's immobility time when tested in FST and TST. The extract did not show anticonvulsant activity, in addition to not improving the memory parameters of animals (IAT) or interfering with their locomotor activity (OFT). Besides, HEPC administration decreased the MAO-A activity and increased the GABA levels in the animal's brain. HEPC induces sedative-hypnotic, anxiolytic-, and antidepressant-like effects. These neuropharmacological effects of HEPC could be, at least in part, related to the modulation of the GABAergic system and/or MAO-A activity.

Anticonvulsant and Anti-anxiety Effects of Royal Jelly in Adult Male Syrian Rats

Objective Royal jelly is a honey bee secretion with beneficial effects on the nervous system. The present study aims to investigate the effects of royal jelly in reducing seizure and anxiety-like behaviors in Syrian rats. Methods This is an experimental study. In the seizure model, 25 male white Syrian rats were randomly divided into five groups: Control, royal jelly 100 mg/kg, royal jelly 200 mg/kg, royal jelly 400 mg/kg, and phenobarbital. After 30 minutes, strychnine was injected to induce seizure in animals. The time of seizure onset, seizure duration, and mortality rate in animals were recorded. In the anxiety model, 35 male white Syrian rats were randomly divided into five groups: Control, royal jelly 50 mg/kg, royal jelly 100 mg/kg, royal jelly 200 mg/kg, and diazepam. Anxiety-like behaviors were examined by using the elevated plus maze (EPM) test. Data analysis was performed using one-way ANOVA, and P<0.05 was statistically significant. Results Royal jelly at doses of 200 and 400 mg/kg delayed the time of seizure onset and reduced the seizure duration compared to the control group (P<0.05). The mortality rate was also reduced after using different doses of royal jelly compared to the control group (P<0.05). Moreover, royal jelly at doses of 50 and 100 mg/kg increased the time spent in the open arms of the EPM platform and the number of entries to the open arms compared to the control group (P<0.05). Conclusion Administration of royal jelly can reduce strychnine-induced seizure and modulate anxiety-like behaviors in rats.

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.

Anticonvulsant activity of Nymphaea lotus Linn. extract in mice: The role of GABAergic-glutamatergic neurotransmission and antioxidant defence mechanisms

Epilepsy remains an unmet medical need affecting more than 50 million people worldwide with about 125,000 mortality annually and more prevalent in low- and middle-income countries. Nymphaea lotus (also known as water lilly) is an aquatic plant used traditionally to treat convulsive episodes in Southwestern Nigeria. This study was undertaken to evaluate anticonvulsant activity of aqueous Nymphaea lotus extract (ANL) and ethanol Nymphaea lotus extract (ENL) on chemical-induced seizures in mice as well as possible mechanisms of action. Vehicle (10 mL/kg, p.o.), ANL (50–200 mg/kg, p.o.), ENL (50–200 mg/kg) or diazepam (5 mg/kg, p.o.) was administered 1 h prior to chemo-convulsant (picrotoxin (PCT), pentylenetetrazol (PTZ), strychnine or N-methyl-D-aspartate (NMDA)) administration. Most effective doses of the extracts were administered to mice after the establishment of temporal lobe epilepsy (TLE) induced by kainic acid. Thereafter, memory assessment in Y-maze, depressive-like behaviour in tail suspension test (TST) and anxiety model in elevated plus maze test (EPM). The prefrontal cortex and hippocampus were assayed for oxidative stress parameters. The pretreatment of mice with ANL or ENL significantly prolonged onset of seizures and reduced the duration of picrotoxin-, pentylenetetrazol-, and strychnine-induced seizures or NMDA-induced turning behaviour. Kainic acid induced spontaneous recurrent seizures and oxidative stress were ameliorated by N. lotus extracts. Moreover, N. lotus-induced anticonvulsant action was reversed by the pretreatment of mice with flumazenil (benzodiazepine receptor antagonist) or L-arginine (nitric oxide precursor). In addition, kainic acid induced neurodegeneration was reduced by N. lotus extract. Findings from this study showed anticonvulsant activity of Nymphaea lotus in neurotoxins-induced seizures through enhancement of inhibitory GABAergic/ antioxidant signalling and inhibition of glutamatergic neurotransmission

Anticonvulsant, Sedative and Antidepressant Effects of Aqueous Extract of &amp;lt;i&amp;gt;Costus afer&amp;lt;/i&amp;gt; Stems in Mice

Epilepsy is a disorder in the nervous system which often causes a loss of consciousness. Traditional treatments are quiet a component of health care system in various populations in spite of the fact that well-established options are available. Most plants are used to treat epilepsy or those which have been verified for anticonvulsant activity were reported. Then, Costus afer is a plant of the Congolese flora used in traditional medicine for its many virtues. Therefore, the anticonvulsant activity of Costus afer was assessed with the strychnine convulsion induction test. Two tests were used for sedative activity such as the barbiturate sleep induction test and motor activity and finally the forced swimming test was also used to assess antidepressant activity. The results showed that the aqueous extract of Costus afer stems had no effects on strychnine-induced seizures at doses of 250 mg/kg and 500 mg/kg compared to the control group. However, the extract of Costus afer stems caused a very significant decrease in motricity at a dose of 500 mg/kg, showing a decrease in the onset time and a very significant increase in sleep duration like the reference molecule such as Diazepam. The aqueous extract of Costus afer stems also caused a decrease in immobility time in mice at a dose of 500 mg/kg.

Potential Mechanisms Involved in the Anticonvulsant Effect of Methanol Extract of Pyrenancantha staudtii in Mice.

To determine the potential effect of Pyrenancantha staudtii extract on experimentally induced seizures in mice and to evaluate the role of benzodiazepines, naloxone, and serotonin within these pathways. Animal behaviours were evaluated using open field, hexobarbitone-induced sleep model, and anticonvulsant activity using picrotoxin-, or strychnine-, or isoniazid-induced convulsions. Attempt to understand the mode of action of the anticonvulsant activity of the plant, three notable antagonists (flumazenil, 3 mg/kg; naloxone 5 mg/kg, i.p., and cyproheptadine, 4 mg/kg, i.p) were used. The results revealed a significant (p < 0.05) reduction in the frequency of rearing and grooming episodes compared with the control. The extract of P. staudtii potentiates the sleeping time of hexobarbitone-induced hypnosis in a dose-related manner. P. staudtii stem bark extracts significantly (p<0.05) prolonged the onset of a seizure and attenuated the duration of seizure in a dose-dependent manner in picrotoxin- and or isoniazid-induced seizures. While, P. staudtii stem bark extract at all doses (100, 200, and 400 mg kg-1) though significantly prolonged the onset of action, but did not confer any significant changes on the duration, as well as mortality in this strychnine-induced seizure model. However, the anticonvulsant activity of the methanolic extract of P. staudtii was significantly reversed following intraperitoneal pre-treatment with flumazenil (GABA receptor antagonist) and naloxone (opioid receptor antagonist) but not cyproheptadine (5-HT2 receptor antagonist) in picrotoxin-induced convulsion. The data obtained suggest that methanol extract of P. staudtii possessed significant anticonvulsant effect, thereby confirming the traditional uses of P. staudtii in the treatment of epilepsy; mechanisms of which could involve the interaction with GABAergic and or opioidergic system.

Evaluation of the neuropharmacological effects of Gardenin A in mice

This work describes the neuropharmacological (sedative, anxiolytic, antidepressant, and anticonvulsant) actions of Gardenin A (GA) (0.1-25 mg/kg p.o.), a flavonoid found in medicinal plants. The sedative effects of GA were assessed with the pentobarbital-induced sleep test. The anxiolytic actions of GA were evaluated with the elevated plus-maze, the light-dark box test, the exploratory cylinder assay, and the open field test. Motor coordination was evaluated with the rotarod test and the open field test. The antidepressant-like actions of GA were evaluated with the tail suspension test and forced swimming test. The mechanisms of the anxiolytic-like and antidepressant-like effects of GA were assessed using inhibitors of neurotransmission pathways. The anticonvulsant activity of GA was evaluated with the strychnine-induced seizure test. The sedative effects of GA were evident only at a dose of 25 mg/kg, which increased the duration of sleep but did not alter sleep onset. GA showed anxiolytic-like actions with activity comparable to that of clonazepam in all experimental tests. The GABAA receptor antagonist bicuculline reversed the anxiolytic-like effects of GA. Furthermore, GA showed significant antidepressant-like actions in both models with activity comparable to that of fluoxetine. Yohimbine, an α2-adrenoceptor blocker, inhibited the antidepressant-like actions of GA. In addition, GA (1-10 mg/kg) did not affect locomotor coordination in mice and delayed the onset of convulsions. These findings suggest that GA induces anxiolytic-like effects and has anticonvulsant actions by the possible involvement of the GABAergic system. The antidepressant-like actions of GA may be mediated by noradrenergic neurotransmission.

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

The Effect of Acute and Chronic Sesame Oil Consumption on the Strychnine Induced Seizure in Adult Rats

The Effect of Acute and Chronic Sesame Oil Consumption on the Strychnine Induced Seizure in Adult Rats

Evaluation and Comparison of Anti-Epileptic Activity of Methanolic Extracts of Seeds of Cuminum Cyminum L. and Centratherum Anthelminticum L. in Seizure Model

Objective: Evaluation and comparison of anti-epileptic activity of methanolic extracts of seeds of Cuminum cyminum L. and Centratherum anthelminticum L. in strychnine-induced seizure model.&#x0D; Methods: The study was conducted in the Department of Pharmacology, University of Karachi. After 15 days of dosing, experiment was performed. A total of 40 healthy mice were selected from animal house of the Pharmacology department, University of Karachi, and were equally divided into four groups. Group 01 was on DMSO (dimethyl sulphoxide) organic solvent as control; Group 02 was on methanolic extract of Cuminum cyminum L. (500 mg/kg); Group 03 was on methanolic extract of Centratherum anthelminticum L. (200 mg/kg) and Group 04 was on reference drug diazepam (3 mg/kg). On the day of experiment, after giving doses of DMSO, methanolic extract of Cuminum cyminum L., methanolic extract of Centratherum anthelminticum L. and diazepam, respectively to all groups, strychnine was administered and animals were observed for latency period and duration of Mortality rate was also evaluated.&#x0D; Results: Group 02 and 03, receiving methanolic extracts of Cuminum cyminum L. and Centratherum anthelminticum L. showed significant seizure protection as observed by delayed seizure onset (p &lt;0.001) and decreased total duration of convulsions in groups 02 and 03 (p£ 0.01, p£ 0.05) respectively. The mortality rate also decreased significantly (p £ 0.05) in comparison with group 01.&#x0D; Conclusion: Anticonvulsant activity of methanolic extracts of Cuminum cyminum L. and Centratherum anthelminticum L. could be due to their antioxidant activity and further enhanced by potentiation of GABAergic and glycinergic activity. Further studies are required to confirm exact mechanism of action.

Quercetin Exerts Anti-convulsant Effects in Animal Model of Grand Mal Epilepsy: Modulation of GABA and Glycinergic Pathways

Quercetin is low molecular weight flavonoid having multiple neuropharmacological actions. Recently, its anticonvulsant effect was reported in rats using electrical kindling models. However, earlier cell culture studies have documented antagonistic action of quercetin on GABAA, GABAC and Glycine channels, which is contrary to recent findings. Hence, the present study aimed at characterizing the effects of quercetin administration in various experimental models of epilepsy. Dose-dependent effects of quercetin on maximal-electroshock seizure (MES) were determined. Further, the effective dose was tested in pentylenetetrazol-induced seizures (PTZ), and strychnine-induced seizures to study the involvement of GABA and Glycinergic receptors. The results revealed a potent anticonvulsant effect of quercetin in MES induced seizures at a dose of 5 and 10 mg/kg. This effect was found to be retained in case of PTZ-induced convulsions and strychnine-induced convulsions (quercetin 10 mg/kg). The present finding warrants further substantiation along with their correlation to molecular mechanism of action.

Anticonvulsant effect of the hydroethanolic leaf extract of Psydrax subcordata (DC.) Bridson in murine models

Ethnopharmacological relevancePsydrax subcordata (DC.) Bridson is a tropical medicinal plant used traditionally for the management of epilepsy. However, there is little scientific evidence to support its use. Aim of studyThe current study investigated the anticonvulsant properties of the hydroethanolic leaf extract of Psydrax subcordata (PSE) in animal models. Materials and methodsThe anticonvulsant effects were evaluated in mouse models of acute seizures (pentylenetetrazole-, picrotoxin-, 4-aminopyridine-, strychnine- and maximal electroshock-induced seizure tests) and status epilepticus (Lithium/pilocarpine-induced SE). The role of GABAergic mechanisms in the actions of the extract was also examined by pre-treatment of animals with flumazenil in the pentylenetetrazole test. ResultsThe extract (30, 100 and 300mg/kg, p.o.) significantly delayed the onset and decreased the duration and frequency of pentylenetetrazole- and picrotoxin-convulsions. PSE also reduced the duration of tonic hind limb extensions in the maximal electroshock-induced seizure test. Furthermore, PSE pre-treatment significantly delayed the onset of seizures and improved survival in the 4-aminopyridine-induced seizure test. In the strychnine-induced seizure test, PSE treatment did not significantly affect the latency to convulsions and time until death when compared to controls. PSE exhibited anticonvulsant effects in the lithium/pilocarpine test by delaying the onset of seizures and status epilepticus as well as reducing the severity of seizures and mortality of mice. Again, the anticonvulsant effect of PSE (100mg/kg, p.o.) was blocked by pre-treatment with flumazenil in the PTZ test. ConclusionPSE has anticonvulsant activity in animal models, and this effect may be mediated, at least partly, through GABAergic mechanisms.

An effector analysis of the interaction of propoxazepam with antagonists of GABA and glycine receptors

Using effector analysis, we studied the mechanism of anti-seizure activity of the alcoxy-derived benzodiazepine (propoxazepam). In models of chemically induced seizures we determined the average molar and weight effective doses (ED50) of propoxazepam as an antagonist of picrotoxin (4.10 ± 0.21 μmol/kg, 1.67 ± 0.09 mg/kg), pentylenetetrazole (2.24 ± 0.93 μmol/kg, 0.9 ± 0.04 mg/kg), and strychnine (40.33 ± 14.91 μmol/kg, 14.24 ± 0.47 mg/kg), which reflect the high activity level of the substance. On the basis of dose–effect curves, using comparative quantile analysis for chemoconvulsants with different mechanisms of action, we showed different stages of interaction of propoxazepam with GABA and glycine receptors under in vivo conditions. We evaluated the partial contribution of myoclonic and toxic components to the general structure of seizures induced by various chemoconvulsants. We believe that the results we obtained indicate that the anti-seizure action of propoxazepam is predominantly mediated by a GABAergic mechanism. Glycinergic components of the inhibition of strychnine-induced seizures by propoxazepam occur at doses that exceed the ED50 and seem to be an additional means of anti-seizure action.

Phenylalanine derivatives with modulating effects on human α1-glycine receptors and anticonvulsant activity in strychnine-induced seizure model in male adult rats

The critical role of α1-glycine receptor (α1-GLYRs) in pathological conditions such as epilepsy is well known. In the present study, structure-activity relations for a series of phenylalanine derivatives carrying selected hydrogen bond acceptors were investigated on the functional properties of human α1-GLYR expressed in Xenopus oocytes. The results indicate that one particular substitution position appeared to be of special importance for control of ligand activity. Among tested ligands (1-8), the biphenyl derivative (2) provided the most promising antagonistic effect on α1-GLYRs, while its phenylbenzyl analogue (5) exhibited the highest potentiation effect. Moreover, ligand 5 with most promising potentiating effect showed in-vivo moderate protection when tested in strychnine (STR)-induced seizure model in male adult rats, whereas ligand 2 with highest antagonistic effect failed to provide appreciable anti(pro)convulsant effect. Furthermore, ligands 2 and 5 with the most promising effects on human α1-GLYRs were examined for their toxicity and potential neuroprotective effect against neurotoxin 6-hydroxydopamine (6-OHDA). The results show that ligands 2 and 5 possessed neither significant antiproliferative effects, nor necrotic and mitochondrial toxicity (up to concentration of 50μM). Moreover, ligand 2 showed weak neuroprotective effect at the 50μM against 100μM toxic dose of 6-OHDA. Our results indicate that modulatory effects of ligands 2 and 5 on human α1-GLYRs as well as on STR-induced convulsion can provide further insights for the design of therapeutic agents in treatment of epilepsy and other pathological conditions requiring enhanced activity of inhibitory glycine receptors.

Anticonvulsant activity of Pseudospondias microcarpa (A. Rich) Engl. hydroethanolic leaf extract in mice: The role of excitatory/inhibitory neurotransmission and nitric oxide pathway

Ethnopharmacological relevancePseudospondias microcarpa (A. Rich) Engl. is a plant used for managing various diseases including central nervous system disorders. Aim of the studyThis study explored the anticonvulsant activity of P. microcarpa hydroethanolic leaf extract (PME) as well as possible mechanism(s) of action in animal models. MethodsEffects of PME was assessed in electroconvulsive (the maximal electroshock and 6-Hz seizures) and chemoconvulsive (pentylenetetrazole-, picrotoxin-, isoniazid-, 4-aminopyridine-, and strychnine-induced seizures) models of epilepsy. In addition, effect of the extract on the nitric oxide pathway and GABAA receptor complex was evaluated. ResultsThe extract (30, 100 and 300mgkg−1, p.o.) significantly delayed the onset as well as decreased the duration and frequency of pentylenetetrazole-, picrotoxin- and strychnine-induced seizures. In addition, PME pre-treatment significantly improved survival in the 4-aminopyridine- and isoniazid-induced seizure tests. Furthermore, the extract protected against 6-Hz psychomotor seizures but had no effect in the maximal electroshock test. The anticonvulsant effect of PME (100mgkg−1, p.o.) was also reversed by pre-treatment with flumazenil, L-arginine or sildenafil. However, L-NAME or methylene blue (MB) augmented its effect. ConclusionResults show that PME has anticonvulsant activity and may probably be affecting GABAergic, glycinergic, NMDA, K+ channels and nitric oxide-cGMP pathways to exert its effect.

Synthesis, molecular modelling, and preliminary anticonvulsant activity evaluation of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4] nonane-3,8-dione derivatives

The synthesis, pharmacological evaluation and molecular modelling study of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives as potential anticonvulsant agents are described. The newly synthesized compounds were characterized by both analytical and spectral data. Alkylation of 1H-imidazole or substituted piperazine with 1-(2-naphthyl)-2-bromoethanone (2) gave naphthalen-2-yl 2-(1H-imidazol-1-yl) acetate (3) and naphthalen-2-yl 2-(substituted piperazin-1-yl) acetate (4–8). Moreover, condensation of naphthalen-2-yl 2-bromoacetate or 2-bromo-1-(naphthalen-2-yl) ethanone with hydrazine hydrate and acetylacetone resulted in the formation of the cyclic pyrazole products 9 and 13. Sonication of naphthalen-2-yl acetate (1) with 2-chloropyridine, 2-chloropyrimidine and 2-(chloromethyl) oxirane gave naphthalen-2-yl 2-(pyridin-2-yl) acetate (10), naphthalen-2-yl 2-(pyrimidin-2-yl) acetate (11) and naphthalen-2-yl-3-(oxiran-2-yl) propanoate (12) respectively. Cyclocondensation reaction of 2-iminothiazolidin-4-one (14) with thioglycolic acid, thiolactic acid and thiomalic acid gave 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives (15–17). The compounds were testedin vivofor the anticonvulsant activity by delaying strychnine-induced seizures. The diazaspirononane (17) and 1-(2-naphthyl)-2-bromoethanone (2) showed a high significant delay in the onset of convulsion and prolongation of survival time compared to phenobarbital. The molecular modelling study of anticonvulsant activity of synthesized compounds showed a CNS depressant activity via modulation of benzodiazepine allosteric site in GABA-A receptors.