Anticonvulsant activity of methanolic extract of Withania cogulans in mice.

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

Pharmacological and toxicological effects of Ruta chalepensis L. on experimentally induced seizures and electroencephalographic spectral power in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ruta chalepensis L. (Rutaceae) is used in traditional medicine to treat a wide variety of disorders such as rheumatism, fever, mental disorders, dropsy, neuralgia, menstrual problems, anxiety, and epilepsy. AIM OF THE STUDY: To evaluate and compare the anticonvulsant properties of an aqueous extract and ethyl acetate (AcOEt) fraction of R. chalepensis on pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) test in mice, by analyzing behavior and electroencephalogram (EEG), as well as GABAA receptors involvement. METHODS: The effect of an acute administration of different dosage of the aqueous extract (300 or 500 mg/kg) or AcOEt fraction (100, 300, 500 or 1000 mg/kg) of R. chalepensis was explored on two different models of acute seizure induction in mice, the PTZ and maximal electroshock (MES) tests. Behavioral and electrographic effects were quantified. Additionally, the possible involvement of the GABAA receptors was explored in the presence of picrotoxin (a non-competitive antagonist of the GABAA receptor). RESULTS: AcOEt fraction of R. chalepensis was more efficient than aqueous extract to reduce the incidence of tonic-clonic seizures and mortality in a significant and dose-dependent manner in both the PTZ and MES tests. This anticonvulsant effect was not abolished in the presence of picrotoxin. The EEG spectral power analysis revealed that aqueous extract decreased alpha and beta power, while AcOEt fraction decreased alpha and gamma power confirming previous findings of its depressant effect in the central nervous system. It is important to mention that the highest dosage of the AcOEt (1000 mg/kg) produced a severe suppression or isoelectric EEG activity (EEG flattening), recognized as a comatose state, suggesting a neurotoxic effect at this dosage. CONCLUSION: Our data reinforce that depressant and anticonvulsant effects of R. chalepensis depend in part on the presence of constituents from medium polarity. We also found that anticonvulsant effect is not mediated by GABAA receptors. In addition, cautious is emphasized when high doses of this natural product are used in traditional medicine since it might produce neurotoxic effects.

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

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

Salvinorin A Does Not Affect Seizure Threshold in Mice.

The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.

Syntheses of Benzo[d]Thiazol-2(3H)-One Derivatives and Their Antidepressant and Anticonvulsant Effects.

Thirty-four new benzo[d]thiazol derivatives 2a-2i, 3a-3r, and 4a-4g were synthesized and investigated for their potential antidepressant and anticonvulsant effects. In a forced swimming test, 2c and 2d showed the highest antidepressant and anticonvulsant effects. 2c and 2d displayed a higher percentage decrease in immobility duration (89.96% and 89.62%, respectively) than that of fluoxetine (83.62%). In the maximal electroshock seizure test, 3n and 3q showed the highest anticonvulsant effect, with ED50 values of 46.1 and 64.3 mg kg-1, and protective indices of 6.34 and 4.11, respectively, which were similar to those of phenobarbital or valproate. We also found that the mechanism for the antidepressant activity of 2c and 2d may be via increasing the concentrations of serotonin and norepinephrine.

Anticonvulsive activity of duloxetine: A new choice for the epileptic patients with depression.

The aim of this study was to investigate the antiepileptic effects of duloxetine in the maximal electroshock test and convulsions induced by four compounds: Pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide, and bicuculline. Duloxetine exhibited moderate anticonvulsive activity with an ED50 (median effective dose) of 48.21 mg/kg in the maximal electroshock test in mice. The anticonvulsive action of duloxetine was also confirmed in chemical-induced seizure tests, where this drug decreased tonic convulsions. Single administration of duloxetine (6.25-25 mg/kg) significantly increased the anticonvulsant effects of valproate, carbamazepine, and oxcarbazepine in the maximal electroshock test. Furthermore, pretreatment with thiosemicarbazide (an inhibitor of GABA synthesis enzyme) significantly increased the ED50 of duloxetine, suggesting the GABAergic system may contribute to the anticonvulsive action of duloxetine. These results support the use of duloxetine in the treatment of coexisting depression and epilepsy.

Antiepileptic Effects of Protein-Rich Extract from Bombyx batryticatus on Mice and Its Protective Effects against H2O2-Induced Oxidative Damage in PC12 Cells via Regulating PI3K/Akt Signaling Pathways.

Bombyx batryticatus is a known traditional Chinese medicine (TCM) utilized to treat convulsions, epilepsy, cough, asthma, headaches, and purpura in China for thousands of years. This study is aimed at investigating the antiepileptic effects of protein-rich extracts from Bombyx batryticatus (BBPs) on seizure in mice and exploring the protective effects of BBPs against H2O2-induced oxidative stress in PC12 cells and their underlying mechanisms. Maximal electroshock-induced seizure (MES) and pentylenetetrazole- (PTZ-) induced seizure in mice and the histological analysis were carried out to evaluate the antiepileptic effects of BBPs. The cell viability of PC12 cells stimulated by H2O2 was determined by MTT assay. The apoptosis and ROS levels of H2O2-stimulated PC12 cells were determined by flow cytometry analysis. Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione (GSH) in PC12 cells were assayed by ELISA and expressions of caspase-3, caspase-9, Bax, Bcl-2, PI3K, Akt, and p-Akt were evaluated by Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR) assays. The results revealed that BBPs exerted significant antiepileptic effects on mice. In addition, BBPs increased the cell viability of H2O2-stimulated PC12 cells and reduced apoptotic cells and ROS levels in H2O2-stimulated PC12 cells. By BBPs treatments, the levels of MDA and LDH were reduced and the levels of SOD and GSH-Px were increased in H2O2-stimulated PC12 cells. Moreover, BBPs upregulated the expressions of PI3K, Akt, p-Akt, and Bcl-2, whereas they downregulated the expressions of caspase-9, caspase-3, and Bax in H2O2-stimulated PC12 cells. These findings suggested that BBPs possessed potential antiepileptic effects on MES and PTZ-induced seizure in mice and protective effects on H2O2-induced oxidative stress in PC12 cells by exerting antioxidative and antiapoptotic effects via PI3K/Akt signaling pathways.

Aqueous Extract of Wood Ear Mushroom, Auricularia polytricha (Agaricomycetes), Demonstrated Antiepileptic Activity against Seizure Induced by Maximal Electroshock and Isoniazid in Experimental Animals.

Auricularia polytricha is a popular mushroom found all over the world. This article describes a study of the antiepileptic effect of A. polytricha, a mushroom that is used traditionally for treating asthma, rheumatism, tumors, cough, fever, and epilepsy, and for its antimicrobial effect. We carried out toxicity studies to identify a standard dose of A. polytricha aqueous extract; maximal electroshock (MES)- and isoniazid (INH)-induced seizures in albino mice were used to screen for the extract's antiepileptic activity. Per Organisation for Economic Co-operation and Development Guideline 423, up to 2000 mg/kg body weight of extract was toxic. Animals were treated with aqueous extract at doses of 200, 400, and 600 mg/kg body weight. Phenytoin was used as the reference anticonvulsant drug for comparison. The investigation found a significant interruption in INH-induced clonic seizure. During MES, we found a reduction in the period of hind leg extensor phase; mice exhibited a significant decrease in the duration of hind limb extension after being treated with 400 and 600 mg/kg doses of A. polytricha. Comparable results were obtained in the INH group, as the extract seemed to delay the onset of a clonic seizure. The aqueous extract of A. polytricha showed antiepileptic action against MES- and INH-induced epilepsy in the mice. This extract, however, requires additional study in order to completely explain its active ingredients and their mechanisms of action.

The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.

Synthesis and anticonvulsant screening of 1,2,4-triazole derivatives.

BACKGROUND: Currently available antiepileptic drugs offer limited symptomatic treatment and fail to cure more than 30% of the epileptic seizures. (Arylalkyl)azoles are a class of anticonvulsants including nafimidone and loreclezole. Here, we report the design and synthesis of new (arylalkyl)azoles in N-[1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine ester structure, their anticonvulsant screening and in silico prediction studies of their pharmacokinetic properties. METHODS: The title compounds were synthesized according to the Steglich esterification of N-[1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine with various carboxylic acids. Anticonvulsant identification and quantification tests were performed in mice by the Epilepsy Therapy Screening Program (ETSP) of the National Institutes of Health (NIH) using 6Hz psychomotor, maximal electroshock (MES), and rotorod tests. Their physicochemical and pharmacokinetic properties were calculated using QikProp. RESULTS: Most of the compounds showed protection against 6Hz- and/or MES-induced seizures. 4a, 4b, and 4g were active at 100mg/kg, 4g was active in both tests without neurotoxicity. According to the QikProp calculations the title compounds were druglike and had some favourable properties such as high membrane permeability and oral absorptivity. CONCLUSION: Anticonvulsant screening of a set N-[1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine esters yielded some active derivatives in 6Hz and MES test. Especially, 4g emerged as a promising compound with activity at 100mg/kg and no toxicity. The compounds were predicted to be drug like and have good pharmacokinetic properties except hERG inhibition, which needs to be addressed in further optimization studies.

A novel metabolism-based phenotypic drug discovery platform in zebrafish uncovers HDACs 1 and 3 as a potential combined anti-seizure drug target.

Despite the development of newer anti-seizure medications over the past 50 years, 30-40% of patients with epilepsy remain refractory to treatment. One explanation for this lack of progress is that the current screening process is largely biased towards transmembrane channels and receptors, and ignores intracellular proteins and enzymes that might serve as efficacious molecular targets. Here, we report the development of a novel drug screening platform that harnesses the power of zebrafish genetics and combines it with in vivo bioenergetics screening assays to uncover therapeutic agents that improve mitochondrial health in diseased animals. By screening commercially available chemical libraries of approved drugs, for which the molecular targets and pathways are well characterized, we were able to reverse-identify the proteins targeted by efficacious compounds and confirm the physiological roles that they play by utilizing other pharmacological ligands. Indeed, using an 870-compound screen in kcna1-morpholino epileptic zebrafish larvae, we uncovered vorinostat (Zolinza™; suberanilohydroxamic acid, SAHA) as a potent anti-seizure agent. We further demonstrated that vorinostat decreased average daily seizures by ∼60% in epileptic Kcna1-null mice using video-EEG recordings. Given that vorinostat is a broad histone deacetylase (HDAC) inhibitor, we then delineated a specific subset of HDACs, namely HDACs 1 and 3, as potential drug targets for future screening. In summary, we have developed a novel phenotypic, metabolism-based experimental therapeutics platform that can be used to identify new molecular targets for future drug discovery in epilepsy.

Protective effect of Terminalia chebula against seizures, seizure-induced cognitive impairment and oxidative stress in experimental models of seizures in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Teminalia chebula (TC) has been traditionally used in the Ayurvedic system of medicine primarily for gastrointestinal disorders. Its fruit extract has also been used to treat epilepsy and other CNS disorders. AIM OF THE STUDY: To evaluate the effect of hydroalcoholic fruit extract of Terminalia chebula (HETC) on experimental models of seizures, seizure-induced cognitive impairment and oxidative stress in rats. MATERIALS AND METHODS: In vitro antioxidant activity of HETC was evaluated by using ABTS, NO and DPPH radical scavenging assay. For in-vivo study, seizures were induced in Wistar rats (200-225g) by pentylenetetrazole (PTZ) and maximal-electroshock. (MES). The anticonvulsant effect of the HETC (250, 500, and 1000mg/kg, orally) was evaluated in seizure models. The therapeutic and sub-therapeutic dose of valproate and phenytoin were also assayed. The potential effect of co-administration of HETC (500mg/kg) with sub-therapeutic dose of valproate and phenytoin were also evaluated in PTZ and MES seizures model respectively. Effect on cognition was assessed using elevated plus maze (EPM) and passive avoidance test (PA). The in- vivo oxidative stress parameters (malondialdehyde and glutathione) were assessed in the cerebral cortex and hippocampus part of rat brain. RESULTS: The IC50 value of HETC in in vitro antioxidant assays i.e. ABTS, DPPH and NO radical scavenging assay was found to be 2.27µg/ml, 6.04µg/ml and 4.37µg/ml respectively. In experimental study, PTZ and MES treated groups exhibited 100% seizures with increased oxidative stress (p < 0.001) and cognitive deficits (p < 0.01) as compared to control group. HETC at highest dose (1000mg/kg) showed 83.33% (5/6) protection in MES induced seizures while 66.66% (4/6) protection in PTZ induced seizures. However, HETC (1000mg/kg) and co-administration of sub-therapeutic dose of HETC with valproate and phenytoin showed complete protection. In addition, it also attenuated the seizure induced oxidative stress and cognitive impairment as indicated by significant (p < 0.01) improvement in the transfer latencies in EPM and PA as compared to PTZ and MES treated group. CONCLUSIONS: The findings suggest that HETC exhibited significant anticonvulsant activity and also potentiated the subtherapeutic dose of phenytoin and valproate indicate its usefulness as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress.

A dangerous context changes the way that rats learn about and discriminate between innocuous events in sensory preconditioning.

Four experiments used a sensory preconditioning protocol to examine how a dangerous context influences learning about innocuous events. In Experiments 1, 2, and 3, rats were exposed to presentations of a tone followed immediately or 20-sec later by presentations of a light. These tone-light pairings occurred in a context that was either familiar and safe, or equally familiar but dangerous, that is, it was a context in which rats had been exposed to footshock. Rats were next exposed to parings of the light and shock and then tested with the tone (and light). The experiments showed that a dangerous context permits formation of a tone-light association under circumstances that preclude formation of that same association in a safe context (Experiments 1 and 2), and that this facilitative effect on associative formation depends on the content being currently dangerous rather than having been dangerous in the past (Experiment 3). Experiment 4 examined whether a dangerous context facilitates discrimination between two innocuous events. In a safe or dangerous context, rats were exposed to a tone that signaled the light and then to a white noise presented alone. Subsequent to conditioning of the light, the tests revealed that rats that had been exposed to these tone-light and white noise alone presentations in a dangerous context froze to the tone but not to the noise, whereas those exposed in a safe context froze to both the tone and the white noise. The results were related to previous evidence that the amygdala is critical for processing information about innocuous stimuli in a dangerous but not a safe context. They were attributed to an amygdala-based enhancement of arousal and/or attention in a dangerous context, hence the facilitation of associative formation and enhanced discriminability in this context.

Evaluation of the Anticonvulsant Effect of Brilliant Blue G, a Selective P2X7 Receptor Antagonist, in the iv PTZ-, Maximal Electroshock-, and 6 Hz-Induced Seizure Tests in Mice.

Epilepsy is one of the most common neurological disorders which is diagnosed in around 65 million people worldwide. Clinically available antiepileptic drugs fail to control epileptic activity in about 30% of patients and they are merely symptomatic treatments and cannot cure or prevent epilepsy. There remains a need for searching new therapeutic strategies for epileptic disorders. The P2X7 receptor has been recently investigated as a new target in epilepsy treatment. Preclinical studies revealed that P2X7 receptor antagonists have anticonvulsant properties in some models of epilepsy. We aimed to investigate whether P2X7 receptor antagonist-brilliant blue G (BBG)-is able to change seizure threshold in three acute seizure models in mice, i.e., in the intravenous pentylenetetrazole seizure threshold, maximal electroshock seizure threshold and 6 Hz psychomotor seizure threshold tests. BBG was administered acutely (50-200 mg/kg, 30 min before the tests) and sub-chronically (25-100 mg/kg, once daily for seven consecutive days). Moreover, the chimney and grip strength tests were used to estimate the influence of BBG on the motor coordination and muscular strength in mice, respectively. Our results revealed only a week anticonvulsant potential of the studied P2X7 receptor antagonist because it showed anticonvulsant action only in the 6 Hz seizure test, both after acute and sub-chronic administration. BBG did not significantly influence seizure thresholds in the remaining tests. Motor coordination and muscular strength were not affected by the studied P2X7 receptor antagonist. In summary, BBG does not possess any remarkable anticonvulsant potential in acute seizure models in mice.

Synthesis and Evaluation of Novel Diazaspiro Hydantoins as Potential Anticonvulsants.

BACKGROUND: Epilepsy, one of the most frequent neurological afflictions in man characterized by excessive temporary neuronal discharges resulting in uncontrolled convulsion, requires special medical attention. Though several new anticonvulsants are introduced, some types of seizures are still not adequately treated with current therapy. Toxicity, intolerance, and lack of efficacy for certain types of seizure are some of the limitations of the current medications. METHODS: Maximal electroshock (MES) seizure model was used in the present study to evaluate the anticonvulsant activity of the drugs. Seizures were induced in ten weeks old male Wistar rats (200-220 g) by delivering electro shock of 150 mA for 0.2 sec by means of a convulsiometer through a pair of ear clip electrodes. The test compounds (1-10, 100 mg/kg) were administered by oral route 30 mins before the maximal electroshock seizure test by suspending in carboxymethylcellulose (1%). The animals were observed closely for 2 mins. The percentage of inhibition of seizure relative to control was recorded and calculated. Phenytoin (100 mg/kg, p.o) was used as a standard drug. The data was analysed by using one way ANOVA followed by dunnett's test. RESULTS: In our present series of compounds the active compounds possess all the requirements essential for anticonvulsant activity as proposed by Dimmock and others. In this study, it reveals that, compounds showing anticonvulsant activity with more lipophilic N-substitution group are more active than hydrophobic substitution in the hydantoin ring. The rapid onset of action is believed to be due to the substitution of more lipophilic propyl group in the N-substitution in the hydantoin moiety. Evidently, this distal hydrophobic centre alters the bioavailability of the molecules. CONCLUSION: The results are encouraging and show that, the hydantoins are more potential molecules for the treatment of anticonvulsant. Anticonvulsants have greatly improved the lives of people with epilepsy. Approximately 70% of patients can achieve complete freedom from seizures with appropriate treatment. Lipophilicity appears to govern the MES activity. If there is lipophilic moiety, then MES activity is favoured. All the compounds have shown promising and significant protective effect on maximal electroshock induced seizures when compared to vehicle treated control rats.

Novel Mannich-bases as Potential Anticonvulsants: Syntheses, Characterization and Biological Evaluation.

BACKGROUND: Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5-benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity. OBJECTIVE: Synthesis, characterization, structure activity relationship and anticonvulsant activity of the Mannich bases of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. METHODS: All the derivatives were synthesized in three steps. In the first step, substituted 4-hydroxy chalconylbenzene was synthesized by the reaction of 4-hydroxyacetophenone and substituted benzaldehyde, in the presence of potassium hydroxide. In the second step, 2,3-dihydro- 1,5- benzothiazepines and 2,3-dihydro-1,5-benzoxazepines were synthesized by the reaction of 2- thio/aminophenol with chalcones in the presence of glacial acetic acid. In the third step, these compounds finally underwent Mannich reaction with different secondary amines to the respective title compounds. All the synthesized derivatives were characterised and evaluated for anticonvulsant activity using MES (Maximal Electroshock Induced Seizure) and INH (Isoniazide Induced Convulsion) models. RESULTS: The synthesized derivatives were found to be more active in the MES model than INH model, with phenytoin and diazepam being the standards respectively. Accordingly, the mode of action of the synthesized compounds may be similar to phenytoin. The methyl piperazine containing compound, at a dose of 30 mg/kg., was found to be the most active and promising compound in the series. CONCLUSION: The benzothiazepine derivatives showed better anticonvulsant activity than the benzoxazepines derivatives.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy.

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.

Trachyspermum ammi Seeds Supplementation Helps Reverse Scopolamine, Alprazolam and Electroshock Induced Amnesia.

The present study was designed to explore the beneficial effects of successive 10 days administration of Trachyspermum ammi seed's powder (TASP) along with diet (at the dose of 0.5%, 1.0% and 2.0% w/w) on learning and memory of mice. A total of 306 mice divided in 51 equal groups were employed in the study. Passive avoidance paradigm (PAP) and Object recognition Task (ORT) were employed as exteroceptive models. The brain acetylcholinesterase activity (AChE), serum cholesterol, brain monoaldehyde (MDA), brain reduced glutathione (GSH) and brain nitrite were estimated and Alprazolam, Scopolamine and Electroshock induced amnesia was employed to describe the actions. Treatment of TASP significantly increased step down latency of PAA and significantly increased discrimination index of ORT in groups with or without amnesia when compared to respective control groups. Furthermore, TASP administration resulted in significant fall in brain AChE activity, brain MDA level and brain nitrite level with simultaneous rise in brain GSH level, thereby decreased oxidative damage. A significant decrease in serum cholesterol was also observed. Ajowan supplementation may prove a remedy for the management of cognitive disorders owing to have pro-cholinergic, antioxidant and hypo-lipidemic activities.

The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?

Epilepsy, a prevalent neurological disease characterized by spontaneous recurrent seizures (SRS), is often refractory to treatment with anti-seizure drugs (ASDs), so that more effective ASDs are urgently needed. For this purpose, it would be important to develop, validate, and implement new animal models of pharmacoresistant epilepsy into drug discovery. Several chronic animal models with difficult-to-treat SRS do exist; however, most of these models are not suited for drug screening, because drug testing on SRS necessitates laborious video-EEG seizure monitoring. More recently, it was proposed that, instead of monitoring SRS, chemical or electrical induction of acute seizures in epileptic rodents may be used as a surrogate for testing the efficacy of novel ASDs against refractory SRS. Indeed, several ASDs were shown to lose their efficacy on acute seizures, when such seizures were induced by pentylenetetrazole (PTZ) in epileptic rather than nonepileptic rats, whereas this was not observed when using the maximal electroshock seizure test. Subsequent studies confirmed the loss of anti-seizure efficacy of valproate against PTZ-induced seizures in epileptic mice, but several other ASDs were more potent against PTZ in epileptic than nonepileptic mice. This was also observed when using the 6-Hz model of partial seizures in epileptic mice, in which the potency of levetiracetam, in particular, was markedly increased compared to nonepileptic animals. Overall, these observations suggest that performing acute seizure tests in epileptic rodents provides valuable information on the pharmacological profile of ASDs, in particular those with mechanisms inherent to disease-induced brain alterations. However, it appears that further work is needed to define optimal approaches for acute seizure induction and generation of epileptic/drug refractory animals that would permit reliable screening of new ASDs with improved potential to provide seizure control in patients with pharmacoresistant epilepsy.