Seizure Test Research Articles

Neuropharmacological and molecular docking studies of xanthones from Swertia corymbosa

Anxiety represents a public health problem consistently found to be the most prevalent class of mental disorders among people of all ages. Xanthones possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study, we aimed to investigate anxiolytic-like antidepressant and anticonvulsant properties of isolated xanthones from Swertia corymbosa. We evaluated anxiolytic-like activity of compounds 1–3 in the mouse elevated plus maze (EPM) and open field test (OF). We examined the influence on locomotor activity in mouse to determine if the effect observed in the actophotometer specific. We used step-through rotarod tests to evaluate the motor function and muscle grip. Compounds 1–3 significantly induced an increase in the number of entries into open arms and a decrease in time spent into closed arms at the dose of 50 mg/kg body weight (BW). The compounds also induced increase of rearing and decrease grooming at the doses of 25 and 50 mg/kg BW during the OF test. In addition, compounds induced a significant increase of time taken to enter at the center of the experimental set at the dose of 50 mg/kg BW during the open field test. The compounds 1–3 significantly delayed the onset as well as decreased the pentylenetetrazole and isoniazid-induced seizure tests. Compound 3 pretreatment significantly improved survivals in pentylenetetrazole and isoniazid-induced seizure tests. In silico studies reveal its possible mechanism of action shed on light to develop novel drugs against CNS disorders.

Effect of Tadalafil on Seizure Threshold and Activity of Antiepileptic Drugs in Three Acute Seizure Tests in Mice

Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with epilepsy.

Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model.

We previously demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate subtype 2 (mGlu2 ) receptors have potential synergistic interactions with the antiseizure drug levetiracetam (LEV). The present study utilizes isobolographic analysis to evaluate the combined administration of JNJ-46356479, a selective and potent mGlu2 PAM, with LEV as well as sodium valproate (VPA) and lamotrigine (LTG). The anticonvulsant efficacy of JNJ-46356479 was evaluated in the 6-Hz model of psychomotor seizures in mice. JNJ-46356479 was administered in combination with LEV using 3 fixed dose-ratio treatment groups in the mouse 6-Hz (44-mA) seizure test. The combination of JNJ-46356479 with LEV was also evaluated in the mouse corneal kindling model. The potential interactions of JNJ-46356479 with the antiseizure drugs VPA and LTG were also evaluated using fixed dose-ratio combinations. Plasma levels were obtained for analysis of potential pharmacokinetic interactions for each combination studied in the mouse 6-Hz model. JNJ-46356479 was active in the 6-Hz model at both 32-mA and 44-mA stimulus intensities (median effective dose = 2.8 and 10.2mg/kg, respectively). Using 1:1, 1:3, and 3:1 fixed dose-ratio combinations (LEV:JNJ-46356479), coadministration was significantly more potent than predicted for additive effects, and plasma levels suggest this synergism was not due to pharmacokinetic interactions. Studies in kindled mice further demonstrate the positive pharmacodynamic interaction of LEV with JNJ-46356479. Using 1:1 dose-ratio combinations of JNJ-46356479 with either VPA or LTG, there were no significant differences observed for coadministration. These studies demonstrate a synergistic interaction of JNJ-46356479 with LEV, whereas no such effect occurred for JNJ-46356479 with either VPA or LTG. The synergy seems therefore to be specific to LEV, and the combination LEV/mGlu2 PAM has the potential to result in a rational polypharmacy approach to treat patients with refractory epilepsy, once it has been confirmed in clinical studies.

Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is also highly associated with autism spectrum disorders (ASD). It is caused by expansion of a CGG repeat sequence on the X chromosome resulting in silencing of the FMR1 gene. This is modeled in the mouse by deletion of Fmr1 (Fmr1 KO). Fmr1 KO mice recapitulate many of the behavioral features of the disorder including seizure susceptibility, hyperactivity, impaired social behavior, sleep problems, and learning and memory deficits. The mammalian target of rapamycin pathway (mTORC1) is upregulated in Fmr1 KO mice and is thought to be important for the pathogenesis of this disorder. We treated Fmr1 KO mice chronically with an mTORC1 inhibitor, rapamycin, to determine if rapamycin treatment could reverse behavioral phenotypes. We performed open field, zero maze, social behavior, sleep, passive avoidance, and audiogenic seizure testing. We found that pS6 was upregulated in Fmr1 KO mice and normalized by rapamycin treatment, but, except for an anxiogenic effect, it did not reverse any of the behavioral phenotypes examined. In fact, rapamycin treatment had an adverse effect on sleep and social behavior in both control and Fmr1 KO mice. These results suggest that targeting the mTOR pathway in FXS is not a good treatment strategy and that other pathways should be considered.

A study of wear mechanism of plain bearing under actual sliding environment

Plain bearings of industrial equipment are damaged by the wear, and it is main causes in the failure phenomena. Thus, inhibition of wear is significant for preventing the failure of machinery, but there are two subjects. The first is to elucidate the wear progress mechanism and to grasp the wear phenomena and the sign before machinery breakdown. The second is to perceive the damage type of equipment and to give the sufficient performance against machinery failure for the bearing. To satisfy these subjects, new tribometer is required, which can reproduce the sliding condition of actual machines. In this study, the authors have developed new tribometer, and carried out three types wear tests. In the initial friction test, there were two wear modes. In seizure test, wear particle was generated as the load increased, and they were buried in the Al alloy bearing.

Neuropharmacological effects of methanolic extract of Clerodendrum viscosum leaves on wistar albino rats

Background: The aim is to study the central nervous system (CNS) depressant, anxiolytic, and antiepileptic activities of methanolic extract of Clerodendrum viscosum (MECV) leaves. Materials and Methods: The study comprised five groups each with 6 Wistar albino rats. The Group 1 or the positive control (phenytoin 30 mg/kg for the epilepsy model, and diazepam 1 mg/kg for the other models), Group 2 or negative control (0.9% NaCl at 10 ml/kg), and Groups 3–5 or the test drug group (MECV at 200, 400, and 800 mg/kg). Actophotometer test, staircase test, maximal electroshock seizure (MES) test, and the thiopentone sodium-induced sleep test, were used to study the various parameters. Results: The actophotometer test, MES, and staircase test (steps climbed) were analyzed using parametric tests. The sleep induction and staircase test (number of rears) were evaluated using nonparametric tests. A dose-dependent significant (P Abbreviations used: GLP: Good laboratory practice; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; IAEC: Institutional Animal Ethical Committee; CNS: Central nervous system; BZDs: Benzodiazepines; IP: Intraperitoneal ANOVA: Analysis of variance; MECV: Clerodendrum viscosum; HLE: Hind limb extension; HLF: Hind limb flexion; NMDA: N-methyl-D-aspartate; MES: Maximal electroshock seizures; MECV: Methanolic extract of Clerodendrum viscosum; GABA: Gamma-Aminobutyric acid; CCK: Cholecystokinin; PME: Pseudospondias microcarpa; ECG: Electrocardiography; REM: Rapid eye movement; NREM: Nonrapid eye movement.

Design, Synthesis and Pharmacological Evaluation of Sulfonamide Derivatives Screened Against Maximal Electroshock Seizure Test

A series of substituted 4-amino-benzene sulfonamides were designed, keeping in view the structural requirement of pharmacophore. Lipinski rule of five has also been calculated; failure to Lipinski rule was not observed. The synthesized compounds were evaluated for anticonvulsant. Docking was performed through AutoDock Vina. Molecules have been screened out through docking. Compounds were synthesized and characterized through IR, 1HNMR, 13C NMR, Mass and elemental analysis. The anticonvulsant activity of the synthesized compounds was assessed using the MES model. In-silico biological activity spectrum, toxicological studies, predicted oral rat LD50 and possible mechanism of action were investigated. The compound, 4-[2-(4-Acetyl-phenylamino)-ethyl]-benzenesulfonamide (K23) is found most active among the synthesized compounds.

Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy.

Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy. A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice. Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses. This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.

Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs

ObjectiveThe appropriate use of analgesic drugs based on their degree of analgesia and adverse effects is important for pain management. Although it has been reported that AM404, a metabolite of acetaminophen, has anticonvulsant effects in several animal seizure models, little is known about the relation between acetaminophen and seizures. We therefore investigated the effects of acetaminophen on seizure susceptibility in several mouse seizure and epilepsy models and compared the effects with those of nonsteroidal anti-inflammatory drugs (NSAIDs). MethodsAnticonvulsant activity was evaluated in ICR mice using maximum electroshock-induced seizure tests and acute pentylenetetrazol-induced seizure tests. Electrical kindling via corneal stimulation and pentylenetetrazol administration were used to establish animal kindling epilepsy models. Proconvulsive activity was examined using an electroconvulsive shock test with low-stimulus currents. ResultsAcetaminophen showed slight, but not statistically significant, anticonvulsant activity in both the maximum electroshock-induced seizure test (300–600mg/kg i.p.) and acute pentylenetetrazol-induced seizure test (100–600mg/kg i.p.). In contrast, acetaminophen exhibited significant anticonvulsant effects in corneal electroshock-kindled and pentylenetetrazol-kindled mice (ED50 values: 251 and 310mg/kg i.p., respectively). When the proconvulsive effects of NSAIDs were examined in the low-current electroconvulsive shock-induced seizure model, the nonselective cyclooxygenase (COX)-1 and COX-2 inhibitors indomethacin, diclofenac, and loxoprofen induced dose-dependent proconvulsant activity. Celecoxib, a COX-2 selective inhibitor, had no proconvulsant activity. ConclusionThese findings suggest that acetaminophen has a significant anticonvulsant effect and that its profile is completely different from that of NSAIDs.

Anticonvulsant Activity of 3-imidazolylflavanones and Their Flexible Analogs: 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones as New Lead Compounds

In the search for new anticonvulsants, the (arylalkyl)azole framework has been considered as a valuable scaffold. Accordingly, a series of trans-3-imidazolylflavanones (1 – 15) and their flexible analogs 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones (16 – 19) containing an (arylalkyl)azole substructure were evaluated for their anticonvulsant activities by using pentylenetetrazole (PTZ) and maximal electroshock (MES)induced seizure tests. Also, the effect of substituent on the pendant phenyl ring and the impact of structural flexibility were investigated. The obtained results revealed that 2-(azol-1-yl)ethanone derivatives 16 – 18 exhibited 50 – 100% protection against MES-induced seizures at a dose of 100 mg/kg. Particularly, compound 16 was found to be significantly active at doses of 10 and 30 mg/kg (25 and 75% protection, respectively). This compound showed full protection at a dose of 100 mg/kg. The structure – activity relationship study revealed that the dichloro substituent in the secondary phenyl ring can improve the anticonvulsant activity. Furthermore, disconnection of the C2 – C3 bond of flavanone in trans-3-imidazolylflavanones results in flexible analogs 1-[(2-benzyloxy)phenyl]-2-(azol-1-yl)ethanones with improved anticonvulsant activity. Docking study of representative compound 16 with possible targets involved in convulsions demonstrated that the GABAA receptors can be considered as the main target for anticonvulsant activity of compound 16.

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.

Synthesis and Evaluation of Novel Diazaspiro Hydantoins as Potential Anticonvulsants.

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. 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. 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. 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.

Neuropharmacological and acute toxicological evaluation of ethanolic extract of Allamanda cathartica L. flowers and plumieride

Psychiatric diseases affect more than 350 million people all over the world, and medicinal plants have been considered the basis for pharmacological research. The study investigates the anticonvulsant and antidepressant-like activities and acute toxicological effects of ethanolic extract of Allamanda cathartica flowers, and plumieride. The extract was analyzed by HPLC and plumieride was isolated. Toxicity studies were carried out on females Wistar rats (2000 mg/kg). Toxicity was evaluated by measuring biochemical parameters and conducting histopathological analysis. For pharmacological evaluation different doses of the extract (100, 150 and 300 mg/kg, p.o.) and plumieride (0.5, 1 and 2 μg/kg, i.p.) were administered before the Forced-Swimming Test (FST), pentylenetetrazole seizure test (PTZT) or Tail-Suspension Test (TST) in mice. Furthermore, hemolytic activity, cytotoxicity and micronucleus test were performed. In addition, mutagenicity and reproductive/developmental toxicity were estimated by TEST-software analysis. Data show that both treatments induce significant antidepressive-like effect in FST and TST, but not anticonvulsant effect. The effect of plumieride last up to 4 h after treatment. No signs of toxicity, mutagenicity, cytotoxicity or hemolytic activity were observed. The TEST-software demonstrated that plumieride present reproductive/developmental toxicity. Together, the data obtained show that the flowers extract and plumieride present antidepressant-like effect and did not present signals of acute toxicity.

Self-reported history of seizure and baseline neurocognitive test performance in student-athletes: an initial investigation

ABSTRACTObjectives: Baseline neurocognitive assessment data can be critical in return to play (RTP) decision-making following a sport-related concussion (SRC). The literature indicates that many modifying factors of SRC have been studied empirically; however, there has been little investigation into the effect of a self-reported history of seizure(s) on baseline neurocognitive test data. The objective of this investigation was to determine whether a self-reported history of seizure(s) is associated with differences in baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) performance.Methods: A retrospective analysis of 18,245 adolescent and young adult athletes’ ImPACT scores was performed. After application of inclusion and exclusion criteria, 7,391 participants were dichotomized into groups based on the presence or absence of a self-reported history of seizure. Participants reporting a history of seizure (n = 60) were matched on multiple variables in a 1:3 ratio with controls (n = 180) without a history of self-reported seizure. Baseline ImPACT composite scores were then compared between groups using either a 2-tailed t-test or a Mann-Whitney U-Test.Results: A significant between-group difference was observed in ImPACT visual motor speed composite scores (35.28 vs. 37.64, p = 0.029, Hedge’s g = 0.327), with the group self-reporting a history of seizure performing at inferior average scores. No significant between-group differences were detected in verbal memory, visual memory, reaction time, impulse control, or total symptom scores.Conclusion: Athletes with a history of self-reported seizure scored significantly lower on ImPACT visual motor speed compared to matched controls. As a solitary finding with a small effect size, the clinical significance of this difference is unclear. Apart from the decrease in visual-motor speed, this preliminary analysis suggests that athletes with a history of seizure might not have significantly different neurocognitive baseline test scores when compared with matched controls. Further empirical investigation is warranted to determine if a history of seizure is a modifying factor for SRC.

Design and synthesis of novel 2-(5-(4-aryl)-4,5-dihydro-1H-pyrazol-3-yl)-1-(substituted aminomethyl)-1H-benzimidazole as potent anticonvulsants

A variety of novel 2-(5-(4-aryl)-4,5-dihydro-1H-pyrazol-3-yl)-1-(substitutedaminomethyl)-1H-benzimidazole 5a–5l have been synthesized from o-phenylenediamine by a multi-step synthesis. Antiepileptic screening of the title compounds was performed using maximal electroshock and subcutaneous pentylenetetrazole seizures tests while the neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 5d, 5e, 5f and 5l were found active in maximal electroshock model; while 5d, 5e, 5f and 5k showed significant antiepileptic activity in subcutaneous pentylenetetrazole seizure model. Further all these five compounds were administered to rats at 30 mg/kg dose in oral route and found that compounds 5e and 5f showed better activity than Phenytoin. These compounds 5e and 5f revealed protection in maximal electroshock after intraperitoneal administration at a dose of 30 mg/kg (0.5 h and 4.0 h). These compounds also provided protection in the subcutaneous pentylenetetrazole seizure at a dose of 100 mg/kg (0.5 h) and 300 mg/kg (4 h).

HBK-14 and HBK-15, triple 5-HT1A, 5-HT7 and 5-HT3 antagonists with potent antidepressant- and anxiolytic-like properties, increase seizure threshold in various seizure tests in mice

Most antidepressants lower seizure threshold, which might be due to the modulation of serotonergic neurotransmission. Here, we investigated the effects of two 5-HT1A, 5-HT7 and 5-HT3 antagonists, i.e., 1-(2-(2-(2,6-dimethylphenoxy)ethoxy)ethyl)-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-{2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15), with antidepressant- and anxiolytic-like properties, on seizure thresholds in three acute seizure tests, i.e., the intravenous pentylenetetrazole, maximal electroshock seizure threshold (MEST), and 6-Hz corneal stimulation test in mice. We also evaluated their affinity for voltage-gated sodium channels. Our results indicate that HBK-14 increased seizure thresholds in three seizure tests in mice, while HBK-15 was active in the MEST and 6-Hz tests. None of the compounds affected neuromuscular strength or motor coordination at active doses. We showed that both compounds had high affinity for voltage-dependent sodium channels, which combined with the influence on 5-HT1A, 5-HT7 and 5-HT3 receptors, might underlie their anticonvulsant effects. Since most antidepressants lower the seizure threshold, the fact that both compounds with potent antidepressant-like activity, increased or had no influence on seizure threshold is worth investigating.

Evaluation of the Anticonvulsant Effect of Brilliant Blue G, a Selective P2X7 Receptor Antagonist, in\xa0the iv PTZ-, Maximal Electroshock-, and 6\xa0Hz-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.

Anticonvulsant Effects of New 1, 4-DihydropyridineDerivatives Containing Imidazolyl Moiety Against Seizures Induced by Pentylenetetrazole and Maximal Electroshock in Mice.

Epilepsy is a chronic disorder of the brain affecting around 50 million people in the world. Up to 30% of epileptic patients do not respond to available drugs and medical therapies. In this paper, anticonvulsant screening of 10 synthesized new derivatives of 1, 4-dihydropyridine-3, 5-dicarboxamides was performed. Anticonvulsant activity was evaluated by intravenous and intraperitoneal pentylenetetrazole and maximal electroshock induced seizures tests. Nifedipine was used as reference drug. Our pharmacological results revealing the compounds 2, 4, 5, and 6 can be effective in both absence and grandmal seizures in human. These pharmacological studies have displayed that these new dihydropyridine derivatives are capable to inhibiting seizures induced by pentylenetetrazole and maximal electroshock in mice efficiently.

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy.

It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing.

Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy.

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.