Convulsions In Mice Research Articles

Synthesis and Evaluation of Anticonvulsant Activity of Some Quinazoline Analogues

Aim: A new series of Quinazoline 4(3H)-one derivative were prepared by reacting quinazoline 4(3H)-one hydrazide with substituted aromatic aldehydes. Quinazoline is used as a potent pharmacological agent with various biological activities such as antimicrobial, antiviral, antitumor, convulsion, anxiety, anti-inflammatory, and analgesic. In this background, we have synthesized a series of Quinazoline 4(3H)-one derivatives (4a-4f) and screened for their anticonvulsant activity. 
 Methods: In this work, Schiff bases were prepared by treating quinazoline 4(3H)-one hydrazide with aromatic aldehydes. Six compounds (4a-4f) were screened for anticonvulsant activity by Isoniazid (INH) and Pentylenetetrazole (PTZ) induced convulsions in mice.
 Results: All the compounds were given satisfactory reaction yields that representing the efficiency of the employed synthetic route. In INH induced convulsion model, delayed the onset of convulsion significantly 4a, 4b, 4d, 4e, 4f when compared to an induction control group. Whereas delayed onset of convulsion was non-significant for 4c. In PTZ induced convulsion model, delayed the onset of convulsion significantly 4a, 4d, 4e, 4f when compared to induction control group. Whereas delayed onset of convulsion was non-significant for 4b and 4c.
 Conclusion: This indicates the anticonvulsant activity to these derivatives which might be due to potentiating GABA activity in the CNS. This anticonvulsant activity was due to presence of electron-donating group like OH, NH2, OCH3 and electron-withdrawing group like CF3 at 2nd and 4th position of aromatic ring attached to hydrazide.

In vivo screening and toxicity studies of indolinone incorporated thiosemicarbazone, thiazole and piperidinosulfonyl moieties as anticonvulsant agents

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

Effects of probiotics on pentylenetetrazol-induced convulsions in mice

ObjectiveThere are some reports of the effect of the gut microbiota on the central nervous system. The aim of this study was to find out the effect of probiotics on pentylenetetrazol (PTZ)-induced convulsions in mice. MethodsThe mice were pretreated with probiotic powder (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum) suspended in normal saline by intragastric gavage (IG-gavage) for 14 (group 1) or 28 (group 2) days prior to injection of PTZ (90 mg/kg, intraperitoneally). Diazepam (DZP, 1 mg/kg, intraperitoneally) was used as the reference drug. The latency and duration of induced convulsion, as well as mortality protection percentage were recorded 30 min after PTZ injection. For the next step, flumazenil (FLZ) was used to block the effect of DZP. ResultsPretreatment with probiotics for 14 or 28 days had not a significant effect on the latency and duration of seizures induced by PTZ. Neither seizure nor mortality was observed in co-administration of probiotics with DZP. FLZ pretreatment decreased the DZP-induced seizure latency; however, FLZ could not have such an effect in probiotic and DZP group. ConclusionProbiotics alone did not show anticonvulsant effects, but enhanced the anticonvulsant effect of DZP; this suggests the involvement of GABAergic system.

Necrostatin-1 prolongs latency to convulsion in mice exposed to high oxygen partial pressure.

Exposure to very high oxygen partial pressure may cause central nervous system oxygen toxicity (CNS-OT). The role of necroptosis in the pathogenesis of CNS-OT is still unclear. In experiment one, male C57BL/6 mice in the oxygen toxicity (OT) group (n = 5) and necrostatin-1 (Nec-1; a necroptosis inhibitor) (1.5 mg·kg-1, intraperitoneal) group (n = 5) were exposed to pure oxygen at 600 kPa, and the latency to tonic-clonic seizure was recorded. In experiment two, mice were divided into three groups: control group (n = 11), OT group (n = 12) and Nec-1 group (n = 12). Nec-1 was intraperitoneally administered 30 min before oxygen exposure. Mice in the OT group and Nec-1 group were exposed to pure oxygen at 400 kPa for 30 min, and then sacrificed; the brain was harvested for the assessment of inflammation, oxidative stress and necroptosis. Experiment one. Nec-1 pre-treatment significantly prolonged the latency to seizure (245 [SD 18] seconds in the OT group versus 336 (34) seconds in the Nec-1 group). Experiment two. Nec-1 pre-treatment markedly reduced inflammatory cytokines and inhibited cerebral necroptosis, but failed to significantly suppress cerebral oxidative stress. These findings indicate necroptosis is involved in the pathogenesis of CNS-OT, and inhibition of necroptosis may prolong seizure latency, but the specific mechanisms should be investigated further.

The Anticonvulsant Effect of Hydroethanolic Leaf Extract of Calotropis procera (Ait) R. Br. (Apocynaceae).

A number of currently used drugs have been obtained from medicinal plants which are a major source of drugs. These drugs are either used in their pure form or modified to a semisynthetic drug. Drug discovery through natural product research has been fruitful over the years. Traditionally, Calotropis procera is used extensively in the management of epilepsy. This study is conducted to explore the anticonvulsant effect of a hydroethanolic leaf extract of Calotropis procera (CPE) in murine models. This effect was evaluated using picrotoxin-induced convulsions, strychnine-induced convulsions, and isoniazid- and pilocarpine-induced status epilepticus in mice of both sexes. The results showed that CPE (100-300 mg/kg) exhibited an anticonvulsant effect against strychnine-induced clonic seizures by significantly reducing the duration (p = 0.0068) and frequency (p = 0.0016) of convulsions. The extract (100-300 mg/kg) caused a profound dose-dependent delay in the onset of clonic convulsions induced by picrotoxin (p < 0.0001) and tonic convulsions (p < 0.0001) in mice. The duration of convulsions was reduced significantly also for both clonic and tonic (p < 0.0001) seizures as well. CPE (100-300 mg/kg), showed a profound anticonvulsant effect and reduced mortality in the pilocarpine-induced convulsions. ED50 (~0.1007) determined demonstrated that the extract was less potent than diazepam in reducing the duration and onset of convulsions but had comparable efficacies. Flumazenil—a GABAA receptor antagonist—did not reverse the onset or duration of convulsions produced by the extract in the picrotoxin-induced seizure model. In isoniazid-induced seizure, CPE (300 mg kg1, p.o.) significantly (p < 0.001) delayed the onset of seizure in mice and prolonged latency to death in animals. Overall, the hydroethanolic leaf extract of Calotropis procera possesses anticonvulsant properties.

Effect of 70% Ethanol Extract and its Solvent Fractions of Artemisia afra (Jacq. Ex Willd.) against Pentylenetetrazole-Induced Seizure in Mice.

Introduction Artemisia afra (Jacq. ex Willd.), commonly called African wormwood, is a highly aromatic perennial herb and a well-known medicinal plant, claimed to be effective and safe in the treatment of epilepsy. The whole-plant extract is traditionally used as an antiepileptic agent in Ethiopia. Aim of the Study. The aim of this study was, therefore, to evaluate the anticonvulsant effect of the hydroethanolic extract and solvent fractions of A. afra whole part in mice. Materials and Methods The effects of A. afra hydroethanolic extract and its solvent fractions were evaluated against pentylenetetrazole- (PTZ-) induced convulsions in mice. The onset and duration of PTZ-induced convulsions were determined with hydroethanolic A. afra extract and its solvent fractions. Data were analyzed using a one-way analysis of variance (ANOVA) followed by post hoc Tukey's multiple comparisons test. p < 0.05 was considered statistically significant. Results The hydroethanolic extract of A. afra, with all the three doses of 250, 500, and 1000 mg/kg, showed a significant delay (504.833 ± 62.835∗ s; p < 0.05∗; 551.833 ± 47.69∗∗ s; p < 0.01∗∗; and 808.333 ± 64.8∗∗∗s; p < 0.001∗∗∗, respectively) in the mean onset of convulsion and a decrease (17.000 ± 1.88∗∗∗ s, p < 0.05∗; 13.000 ± 1.8∗∗ s, p < 0.01∗∗; and 7.833 ± 1.07∗∗∗ s, p < 0.001, respectively) in the mean duration of convulsion against PTZ-induced convulsion in a dose-dependent manner compared to the control (92.833 ± 13.006 s; 34.167 ± 3.683 s), and its anticonvulsant activity was significantly less compared to that of diazepam (1001.167 ± 68.430 s; 4.500 ± 0.619 s). The solvent fractions, however, did not show anticonvulsant activity against PTZ-induced convulsion. Conclusion Crude extract of A. afra has an anticonvulsant effect in mice. This might be attributed to the synergistic effects of two or more active ingredients present in the herb.

Delta Opioid Receptor (DOR) Agonist Activity of Buprenorphine in Mice

Buprenorphine is an approved method of treatment for opioid use disorder (OUD), and it is under investigation for cocaine use disorder-- for which there are no FDA-approved, pharmacological treatments. Buprenorphine is considered a mixed efficacy opioid ligand, and its partial agonist activity at the mu opioid receptor (MOR) is thought to mediate the therapeutic effects for OUD. There is also evidence that it acts as a kappa opioid receptor (KOR) and delta opioid receptor (DOR) antagonist and a nociception/orphanin FQ receptor (NOPR) agonist. However, one recent report found buprenorphine to act as a partial DOR agonist in cells expressing human opioid receptors (Bidlack et al., 2018). The goal of the present study was to investigate the in vivo activity of buprenorphine at DOR in rodents. Male C57BL6/N mice were used to evaluate the effects of buprenorphine on pentylenetetrazol (PTZ)-induced convulsive activity and in the mouse forced swim test. Buprenorphine did not produce overt convulsions in mice but dose-dependently increased PTZ-induced convulsions with 32 mg/kg buprenorphine as the maximally effective dose, and these effects were attenuated by the DOR antagonist naltrindole. Also, buprenorphine (0.01-0.1 mg/kg) decreased immobility in the mouse forced swim test, which was blocked by pretreatment with naltrindole. Together, these data demonstrate that buprenorphine produces DOR-mediated antidepressant-like effects and potentiates PTZ-induced convulsions, suggesting that buprenorphine acts as a partial DOR agonist in mice. Interestingly, there is a large separation between doses that produce potential antidepressant-like effects and pro-convulsive effects. Future studies will investigate whether this large separation between DOR-mediated effects are due to the complex pharmacology of buprenorphine. Further, these data offer additional insight into the activity of buprenorphine, which could help elucidate the mechanism needed for successful treatment of opioid or cocaine use disorder. These studies were supported in part by R21 DA041565 and DA007315.

Strain Differences in the Delta Opioid Receptor Agonist Properties of the Multifunctional Opioid Glycopeptide MMP2200

Mu-opioid receptor (MOR) agonists, such as morphine, are clinically effective analgesics but present a host of serious side effects including constipation, respiratory depression, tolerance, and dependence. Therefore, there is a clinical need for safer and more effective analgesics for the treatment of chronic pain. Previous literature has provided evidence that coactivation of mu and delta opioid receptors (MOR, DOR, respectively) produce antinociceptive effects with reduced side effects. MMP2200, or lactomorphin, is a glycosylated peptide based on the structure of enkephalin and has been demonstrated to have equal affinity for DOR and MOR in vitro. A previously published study characterized the MOR effects in vivo. However, little is known about the DOR-mediated effects. Therefore, the goal of this study was to assess DOR-mediated behaviors in male and female C57BL/6N and ICR mice. We hypothesized that MMP2200 would produce DOR-mediated convulsions and antidepressant-like effects in the mouse forced swim test in both mouse strains. Male and female C57BL6/N and ICR mice (Envigo) were individually and continuously observed for 30-60 min in clear observation cages, and all behavioral changes were noted. Latency to convulse and duration of convulsion and catalepsy were recorded, and a modified Racine score was used to assess severity of convulsions. Antidepressant-like effects were measured in the forced swim test (6 min, 25°C, 3-4 L tap water) in C57BL6/N mice. MMP2200 produced dose-dependent, DOR-mediated convulsions in both male and female C57BL6/N mice but did not produce convulsions in ICR mice up to the largest doses tested (100 mg/kg). Further, MMP2200 did not enhance the convulsive effects of pentylenetetrazol (PTZ) in ICR mice, unlike other DOR agonists such as SNC80. MMP2200 did not alter immobility in the mouse forced swim test, suggesting that it does not have antidepressant-like effects in C57BL6/N mice. Additionally, no antidepressant-like effect was revealed by blocking the MOR with the irreversible antagonist bFNA (32 mg/kg, 48 h). In summary, MMP2200 produced strain-dependent convulsive effects but no antidepressant-like effects. This unique profile suggests that DOR-mediated behavioral effects of multifunctional opioid ligands may be different than those produced by selective DOR agonists, and future studies will examine the role that the MOR agonist properties may play in mediating these effects. Finally, these results highlight the importance of strain differences when assessing DOR agonist activity in vivo.

Novel Protection by Omega-3-FAs against Strychnine-Induced Tonic-Convulsion in Mice: Synergy with Carbamazepine

Background/Aim: The utility of ω-3-FAs (DHA and EPA) against epilepsy was evident in clonic-convulsion animal-models, in their chronic- than acute-modes. However, their efficacy against tonic-convulsion-models remained unclear. Besides, while some-antiepileptics (AEDs), like carbamazepine (CBZ), adversely impacted the bioavailability of dietary ω-3-FAs, it remains unclear whether co-ω-3-FAs may change efficacy/blood-levels of CBZ. This work investigated the capacity of both acute- versus chronic-regimens of ω-3-FAs to: 1) alleviate the-tonic, strychnine-induced convulsions in mice, and 2) synergize with CBZ-evoked anti-tonic-convulsions, and then further-probe whether this has altered plasma-CBZ levels (clearance).

Experimental evaluation of anticonvulsant activity of calcium channel blocker - cinnarizine alone and in combination with N-methyl-D-aspartate receptor antagonist ketamine in mice

Background: Epilepsy disease is a chronic condition of the brain affecting the global population and ranked as the world’s second most common neurological disorder, characterized by recurrent seizures. Despite enormous research advances in the treatment field of epilepsy, conventional antiepileptic drugs failed as a better treatment strategy. These limitations emphasized the necessity for exploring the drugs which make the treatment of epilepsy more effective. In our study, cinnarizine, a calcium channel blocker, and Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, are used alone and in combination to evaluate their effectiveness in treating epilepsy by controlling seizures. Aim and Objectives: The aim of the study was to evaluate the anticonvulsant activity of calcium channel blocker, using cinnarizine alone and in combination with NMDA receptor antagonist ketamine by producing pentylenetetrazol (PTZ)-induced convulsions in male albino mice. Materials and Methods: Anti-convulsant activity of calcium channel blocker, using cinnarizine alone and in combination with ketamine by producing PTZ induced convulsions in male albino mice species was studied. Institutional Animal Ethics Committee permission was acquired before the commencement of the experimental study. Thrity male albino mice (body weight – 24–40 g) were separated into five groups with the allocation of six mice in each group. Group 1 (Control group) received 0.5 ml distilled H2O, Group 2 (Standard group) received 150 mg/kg of sodium valproate dose, Group 3 (Test group 1) received 30 mg/kg of Cinnarizine, Group 4 (Test group 2) received 50 mg/kg of Ketamine, and Group 5 (Test group 3) received cinnarizine (30 mg/kg) and Ketamine (50 mg/kg) combination. After 30 min of administration of control (0.5 ml distilled water), standard drug, and test drug, male albino mice were injected, PTZ (60 mg/kg), subcutaneously and were monitored. The mean time of onset of convulsion (seconds) mean duration of convulsion, and percentage of protection readings were recorded for 1 h. Results: Group 1 (Control group) displayed 0% protection from convulsions and Group 2 (Standard group) exhibited 100% and Group 5 (Test group 3) (T3) exhibited 66.66% protection from convulsions, indicating that the combination of cinnarizine (30 mg/kg) and ketamine (50mg/kg) was effective in PTZ-induced seizures in male albino mice. Conclusion: The anticonvulsant property of cinnarizine and ketamine was less effective when used alone whereas combination was effective, supporting rational use of polytherapy in the treatment of epilepsy.

English

Chemical investigation of the crude methanol/methylene chloride (1:1) extract of the seeds of Harungana madagascariensis resulted in the isolation of two known compounds namely n-dotriacontane and friedelan-3-one. The structures of the isolated compounds were determined on the basis of 1D NMR spectroscopy and comparison with literature data. The crude extract and the two compounds were evaluated for their anticonvulsant effects on pentylenetetrazole or picrotoxin induced convulsions in mice. All the tested treatments showed anticonvulsant effects on experimental models of epileptic seizures chemically induced in mice. Friedelan-3-one and the crude extract showed up to 83% protection of animals against convulsions while n-dotriacontane produced a maximum of 33% protection. Key words: Harungana madagariensis extracts, friedelan-3-one, n-dotriacontane, anticonvulsant activity. &nbsp

Antiepileptic and Antidepressant Activity of Majoon Najah (A Traditional Unani Formulation) in Experimental Animals

Background: Majoon Najah is a polyherbal traditional Unani formulation recommended for the treatment of neurological disorders. To evaluate antiepileptic and antidepressant activity of majoon najah and majoon najah extract in experimental animals. Methods: Anticonvulsant activity was tested using maximal electroshock induced convulsion in male sprague dawley rats using diazepam 3 mg/kg, p.o. as positive control. Pentylenetetrazole induced convulsion in swiss male albino mice was performed using phenytoin 25 mg/kg i.p. as positive control. The antidepressant activity of MN was evaluated using forced swim test model in male using Imipramine 20 mg/kg, p.o. as positive control. Results: Antiepileptic study data showed reduction of all parameters like, tonic hind limb extension, clonic convulsion and stupor; however the values were not found statistically significant at all tested dose levels. The results of forced swim test model indicated that majoon najah effectively showed significant (P<0.001) reduction in immobility duration in animals treated with majoon najah classical at dose 500 mg/kg bw and 1000 mg/kg bw as compared to control rats. Conclusion: Based on above findings, it may be concluded that majoon najah did not showed effectiveness in epilepsy however, the results evident that majoon najah is a potential Unani formulation having antidepressant activity which may be preferred as an alternative therapy over modern medicine to treat depression.

Methyl jasmonate delays the latency to anoxic convulsions by normalizing the brain levels of oxidative stress biomarkers and serum corticosterone contents in mice with repeated anoxic stress.

Repeated exposure to anoxic stress damages the brain through cortisol-mediated increases in oxidative stress and cellular-antioxidants depletion. Thus, compounds with antioxidant property might confer protection against anoxic stress-induced brain injuries. In this study, we further examined the protective effect of methyl jasmonate (MJ), a potent anti-stress agent against anoxic stress-induced convulsions in mice. Thirty-six male Swiss mice randomized into six groups (n=6) were given MJ (25, 50 and 100mg/kg, i.p.) or vehicle (10mL/kg, i.p.) 30min before 15min daily exposure to anoxic stress for 7days. The latency(s) to anoxic convulsion was recorded on day 7. The blood glucose and serum corticosterone levels were measured afterwards. The brains were also processed for the determination of malondialdehyde, nitrite, and glutathione levels. Methyl jasmonate (MJ) delayed the latency to anoxic convulsion and reduced the blood glucose and serum corticosterone levels. The increased malondialdehyde and nitrite contents accompanied by decreased glutathione concentrations in mice with anoxic stress were significantly attenuated by MJ. These findings further showed that MJ possesses anti-stress property via mechanisms relating to the reduction of serum contents of corticosterone and normalization of brain biomarker levels of oxidative stress in mice with anoxic stress.

Evaluation of Hydro-alcoholic Extract of Clerodendrum myricoides (Hochst. Vatke) Leaves and Its Solvent Fractionsin Pentylenetetrazole-Induced Convulsion in Mice

Introduction: Epilepsy is a chronic neurological disorder that affects people of all ages. Herbal medicines are widely used across the globe due to their wide applicability and therapeutic efficacy. The low side effects of traditional herbal medicines have encouraged many types of research into antiepileptic activity. Clerodendrum myricoides is a plant whose leaves extract is traditionally used as an anticonvulsant in Ethiopia. &#x0D; Objective: The point of this investigation was to assess the anticonvulsant effect of the hydro-alcoholic extract and solvent fractions of C. myricoides leaves against pentylenetetrazole-induced seizures in mice. &#x0D; Methods: Comparison of mean latency to onset of convulsion, mean duration of convulsions, and the proportion of percentage protection against seizure of the plant extract was tested against PTZ-induced seizures. Three different doses were used by giving them orally 30 minutes before subcutaneous pentylenetetrazole (80 mg/kg) administration with the positive (diazepam 2 mg/kg) and negative (physiological saline 10 mg/kg) control groups. Data were presented as the mean ± standard error of the mean and analyzed using a one-way analysis of variance (ANOVA) and followed by post-hoc Tukey’s multiple comparisons test. Fisher’s exact test was used for the percentage protection. P &lt; 0.05 was considered statistically significant.&#x0D; Results: The crude extract of C. myricoides, with the doses of 300, 600, 1,200 mg/kgshowed a significant delay in mean latency to onset of seizures [299.33±30.129 sec (p&lt; 0.05); 387.167± 27.6 sec (p&lt;0.01); 417.833±31.9 sec (p&lt;0.001); respectively)]; decrease in the duration of convulsion [27.333±1.585 sec (p&lt;0.05); 16.833±1.537 sec (p&lt;0.01); 10.50±0.671 sec (p&lt;0.001) respectively]; and a proportion of percentage protection of mice against seizure [16.33% (1/6) (p&lt; 0.05); 33.33% (2/6) (p&lt;0.01); 50% (3/6) (p&lt;0.001) respectively] in a dose-dependent manner compared to the control group [92.833±13.006 sec; 34.167±3.683 sec, 0% respectively]. C. myricoides anticonvulsant activity was less than that of diazepam [1001.16± 68.430 sec, 4.500±0.619, 83.33 sec, 83.33% respectively for the doses]. Its solvent fractions, however, didn’tshow a significant anticonvulsant effect.&#x0D; Conclusion: The hydroalcoholic leaves crude extract of C. myricoides has anticonvulsant activity but its solvent fractions do not have comparable significant effects.

Computational and Pharmacological Investigation of (E)-2-(4-Methoxybenzylidene)Cyclopentanone for Therapeutic Potential in Neurological Disorders.

PurposeThis study involved the computational and pharmacological evaluation of (E)-2-(4-methoxybenzylidene)cyclopentan-1-one (A2K10).MethodsIn silico studies were conducted through virtual screening. Morris water and Y-maze tests were conducted to evaluate Alzheimer’s disease. Acute epilepsy haloperidol,and hyperalgesia were used to calculate the epilepsy model, with Parkinson’s disease and mechanical allodynia at a dose of 1–10 mg/kg in the mouse model.ResultsA2K10 exhibited the highest binding affinity against α7 nicotinic acetylcholine receptors (−256.02 kcal/mol). A2K10 decreased escape latency in the Morris water test during different trials. In the Y-maze test, A2K10 dose-dependently increased spontaneous alteration behavior, with maximum effect of 75.5%±0.86%. Furthermore, A2K10 delayed onset of pentylenetetrazole-induced myoclonic jerks and tonic–clonic seizures and decreased duration of tonic–clonic convulsions in mice, with maximum effect of 93.8±5.30, 77.8±2.91, and 12.9±1.99 seconds, respectively. In the haloperidol-induced Parkinson’s disease model, A2K10 significantly prolonged hanging time and reduced tardive dyskinesia. Moreover, A2K10 extended latency in hot-plate hyperalgesia and increased the paw-withdrawal threshold in mechanical allodynia. In toxicity studies, no mortality was observed.ConclusionOverall, the results indicated that A2K10 has potential as an anti-Alzheimer’s, antiepileptic, antiparkinsonian, and analgesic therapeutic compound.

Studying the anticonvulsive activity of new ligands of NDMA-receptor complex – imidazole-4,5-dicarbonic acid derivatives

NMDA receptors were proven to play a significant role in the processes of epileptogenesis. Experimental data indicate a significant anticonvulsant effect of NMDA receptor antagonists, but the use of the studied NMDA ligands remains limited due to their low efficiency and toxic effects. The aim of the study was to investigate the anticonvulsant effect of new ligands of the glutamate NMDA receptor complex imidazole-4,5-dicarboxylic acid (IDA) derivatives on a model of NMDA-induced convulsions in mice. The tested agents (IEM2258 and IEM2248) were injected into the lateral ventricles of a waking mouse brain at doses of 0.10.5 mmol in 5 l 15 minutes before the convulsant (NMDA). Valproic acid was used as a comparator drug. The results of the study showed that IDA derivatives exhibit anticonvulsant activity of various degrees of severity. A pronounced anticonvulsant effect was established for IEM2258 at a dose of 0.4 mmol: a significant reduction in the duration of convulsions (compared to the previous dose of the tested substance) and a total absence of NMDA-induced deaths. IEM2248 showed anticonvulsant activity at a dose of 0.2 mmol, in 100% of cases preventing fatal outcomes and completely protecting animals from the convulsions. Thus, the data obtained in this study showed dose-dependent anticonvulsant effect of new IDA derivatives (IEM2258 and IEM2248) due to the blockade of the NMDA receptor complex, that indicates the promising aspect for the development of these agents and further searching for effective and safe anticonvulsants among this pharmacological class.

Characterization of Delta Opioid Receptor Activity of MMP2200, a Mixed Efficacy Mu and Delta Opioid Receptor Agonist

Pharmacological modulation of the delta opioid receptor (DOR) in conjunction with a mu‐opioid receptor (MOR) agonist produces antinociceptive effects with potentially a better side effect profile. MMP2200 (a.k.a.Lactomorphin) is a CNS permeable, glycosylated peptide and an agonist at both MORs and DORs. Previous reports characterized the MOR agonist effects of MMP2200; however, the DOR agonist effects of MMP2200in vivo have not been explored. DOR agonists, such as SNC80, have been shown to produce convulsions and discriminative stimulus effects in rodents. Therefore, based on the DOR agonist activity of MMP2200, we hypothesized that MMP2200 would produce DOR‐mediated convulsions in mice and SNC80‐like discriminative stimulus effects in rats. Convulsions were evaluated by continual observation for up to 60 min in an observation cage. For SNC80 discrimination experiments, rats were trained to discriminate an injection of 3.2 mg/kg SNC80 from saline under a fixed ratio 10 schedule of food reinforcement, and different doses of SNC80 or MMP2200 were substituted to evaluate percent generalization and response rates. MMP2200 produced brief, non‐lethal convulsions in C57BL/6N, but not ICR, mice that were blocked by the DOR antagonist naltrindole and by genetic deletion of DOR, indicating that MMP2200‐induced convulsions are DOR mediated. Following acute drug administration, mice were then given a second dose of the DOR agonist 24 h later. These mice were tolerant to convulsions induced by SNC80, but not to MMP2200‐induced convulsions. Tolerance to the convulsive effects of MMP2200 was apparent 8 h following the initial injection. SNC80 induced convulsions were enhanced in mice lacking arrestin 2 but were unaltered in mice lacking arrestin 3. However, MMP2200‐induced convulsions were attenuated in mice lacking either arrestin 2 or 3. In rats trained to discriminate SNC80, MMP2200 fully generalized to the discriminative stimulus effects of SNC80 and only slightly decreased rates of responding. Overall, these results demonstrate that the dual MOR/DOR agonist MMP2200 produces many behavioral effects that are similar to the prototypical DOR agonist SNC80. Interestingly, there are some distinct differences in these DOR agonist effects, which may be mediated by concurrent MOR agonist activity with MMP2200 or by activating differential intracellular signaling molecules downstream of DOR activation. Future studies will evaluate the effects of DOR agonists and signaling pathways mediating these effects.

Panax Ginseng Inhibits Maximal Electroshock Induced Convulsions in Mice

Epilepsy is a serious common neurological disease. Panax ginseng root has been identified as a potential therapy for many disorders. The present study investigated the possible anticonvulsant activity of Panax ginseng on maximal electroshock (MES) induced seizure in mice. Mice were divided into the following groups: Group A (control group): injected with normal saline then exposed to electric shock. Group B (test group): injected with sodium valproate (300 mg/kg, 600 mg/kg, 900 mg/kg). Then exposed to electric shock. Group C (test group): injected with Panax Ginseng (150, 250, 350 mg/kg) then exposed to electric shock. All animals were examined for motor coordination on rotarod test. We concluded that P. ginseng at moderate and high doses significantly decreased the HLE duration of convulsion in mice, denoting that P. ginseng has anticonvulsant effects. the antiepileptic activity of P. ginseng might be due to its antioxidative actions, anti-inflammatory, its regulating effect on sodium ion channels and/or due to its possible modulation of GABA receptor channel activity for further investigations.

Evaluation of Anticonvulsant and Antioxidant Activity of Flacourtia indica on Pentylenetetrazole (PTZ) Induced Convulsions in Mice

Evaluation of Anticonvulsant and Antioxidant Activity of <i>Flacourtia indica</i> on Pentylenetetrazole (PTZ) Induced Convulsions in Mice

Evaluation of Anticonvulsant Activity of Ethanolic Extract of Leaves of Cajanus cajan (L) Millsp. In Rodents

Cajanus cajan (L) Millsp. is the perennial plant belongs to family Fabaceae, commonly called as Pigeon pea plant. The presence of phytoconstituents like flavonoids, the flavanone (substituted) from Cajanus cajan (L) Millsp. have in vitro neuroactive property. This flavanone named as pinostrobin helps to inhibit voltage – gated sodium channels. Because of its bioactive phytoconstituents it may act as antiepileptic drug. To avoid problems like ADR herbal plant might be alternative to treat epilepsy. The current study was therefore carried out to evaluate antiepileptic activity of Ethanolic extract of leaves of Cajanus cajan in rodents. The effect of ELECC in MES-induced convulsions in rat and PTZ-induced convulsion in mice was evaluated using doses 100 mg/kg and 200 mg/kg for 7 days. Phenytoin (25 mg/kg), Diazepam (4 mg/kg) was used as standard drug for respective model. Depending on the model, outcome measures were abolishment of Hind Limb Tonic Extensor phase in MES-induced convulsion in rat and onset of latency, recovery or death in PTZ-induced convulsion in mice as well as biochemical estimation of amino acid neurotransmitter (GABA, Glutamate) were evaluated. The ELECC at doses 100 and 200 mg/kg significantly delayed the HLTE phase in MES-induced convulsions in rat whereas, significantly increased onset of latency in PTZ-induced convulsion in mice. It also showed significant (p&gt;0.0001) effect on the level of GABA and Glutamate in dose dependent manner in both models. The phytochemical study of C. cajan showed the presence of Glycosides, Flavonoids, Flavonones, Steroids, Tannins, Fixed oil, Fatty acids and Proteins. As the flavonoids present in C. cajan may contribute to the anticonvulsant activity of the plant. Therefore, the presence of such compounds in the extract may be responsible for the anticonvulsant effect. Therefore, present study validates its anticonvulsant activity. Further, research is required to elucidate its specific mechanism of action and isolation of responsible active principles.