The Effects and Mechanisms of Action of TC-G 1008, GPR39 Agonist, in Animal Models of Seizures and Epilepsy

Background and purpose: The G-protein coupled receptor 39 (GPR39) may be activated by zinc ions. Activation of GPR39 was suggested as a novel pharmacological strategy for treating seizures. Experimental approach: We utilized a specific agonist of GPR39, TC-G 1008, and the nonspecific agonist, zinc chloride and a variety of models of acute seizures or a chronic model of epilepsy which were induced in non-genetically modified mice, GPR39 knockout mice or in zebrafish larvae. We examined total serum zinc (by Inductively Coupled Plasma Optical Emission Spectrometry) as well as intracellular zinc ([Zn2+]I) (by Zinpyr-1 staining) concentrations and the expression of selected proteins (by Western blot) which are associated with GPR39 signaling in the hippocampus. Key results: Liquid chromatography tandem mass spectrometry analysis showed that TC-G 1008 is brain penetrant. TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure (MES) threshold test, but it increased the seizure threshold in the 6-Hz induced seizure threshold test. The behavioral effects of TC-G 1008 and MES or 6-Hz seizure were accompanied by alterations in hippocampal [Zn2+]I. TC-G 1008 increased the mean duration of EEG discharges in response to pentylenetetrazole (PTZ) in zebrafish larvae and facilitated the development of PTZ kindling in mice. Using GPR39 knockout mouse line, generated by the CRISPR-Cas-9 method, we showed that GPR39 is a target for TC-G 1008 regarding PTZ-induced epileptogenesis. Conclusion and implications: Our in vivo data obtained using TC-G 1008 generally argue against GPR39 activation as a therapeutic strategy for alleviating seizures/epilepsy.

Evaluation of Antiepileptic activity of Mosapride in Albino wistar rats

Serotonin causes a significant shift in the excitability of neurons and endogenous serotonin and drugs acting on serotonergic receptors play a role in pathogenesis of epilepsy. This study was done to study the effect of Mosapride, a serotonin receptor 5HT4 agonist, in animal models of epilepsy. Albino Wistar rats were divided into 5 groups with six animals in each group. Group 1 was control group, group 2 was standard group and group 3, 4 and 5 received test drug mosapride in low dose (3mg/kg), high dose (6mg/kg) and mosapride plus standard antiepileptic drug respectively. The antiepileptic efficacy was evaluated using Maximal Electroshock Seizure model (MES) and Pentylenetetrazole (PTZ) induced convulsions. Data was analysed using ANOVA followed by post hoc Tukeys test. Mosapride treated animals showed statistically significant decrease (p<0.001) in the duration of flexion, hind limb extension and post ictal depression in MES model which was comparable to phenytoin group. In PTZ model, mosapride alone did not show any significant difference as compared to control group in terms of latency and duration of seizures (p>0.05). The antiepileptic efficacy of mosapride is similar to phenytoin in MES model. However, in PTZ model mosapride did not show any beneficial antiepileptic effect

Reductions in Hydrogen Sulfide Precede Onset of Mitochondrial Quality Control in the Corneal Kindled Mouse Model of Epilepsy

Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S), a gasotransmitter, promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures and during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS subsequent to acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the corneal kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels in whole brain homogenate and expression of related genes in corneal kindled mice were not altered. However, plasma H2S and MeSH levels were significantly lower during kindling, but not after established kindling. Morever, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, Opa1, Mfn2, Drp1, and Mff during kindling, which did not correlate with gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.

Synthesis, Spectral Characterization and Anticonvulsant Studies of the Novel Triazolothiadiazoles Bearing Benzoxazole Moiety

In this study, new fused triazolo-thiadiazoles (4a-o) were synthesized viamethyl 2-[bromo(phenyl)methyl]-1,3-benzoxazole-5-carboxylate. The structure of novel derivatives was recognized on the basis of spectral data results and screened their anticonvulsant action by means of maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ) procedures. Minimal motor studies were completed by a rotarod method. Compounds 4e, 4g, 4j, 4l, 4m and 4n showing better anticonvulsant action corresponding to hydrophobicity. Other molecules remained fewer lipophilic and have less effectiveness. Most of the compounds positively tolerable the rotarod test deprived of motor deficiency. In conclusion, the prepared derivatives with distal aryl moiety exhibited higher lipophilic character and lead to improved pharmacological achievement, which can be a forthcoming promise.

Effect of Ellagic Acid on Seizure Threshold in Two Acute Seizure Tests in Mice

Ellagic acid (EA) is a natural dietary polyphenol that has many beneficial properties, including anti-inflammatory, antioxidant, antiviral, antibacterial, and neuroprotective effects. Studies have revealed that EA may modulate seizure activity in chemically induced animal models of seizures. Therefore, the aim of the present study was to investigate the effect of EA on the seizure threshold in two acute seizure tests in male mice, i.e., in the intravenous (i.v.) pentylenetetrazole (PTZ) seizure test and in the maximal electroshock seizure threshold (MEST) test. The obtained results showed that EA (100 mg/kg) significantly elevated the threshold for both the first myoclonic twitch and generalized clonic seizure in the i.v. PTZ seizure test. At the highest dose tested (200 mg/kg), EA increased the threshold for tonic hindlimb extension in the MEST test. EA did not produce any significant changes in motor coordination (assessed in the chimney test) or muscular strength (investigated in the grip-strength test). The plasma and total brain concentration-time profiles of EA after intraperitoneal and oral administration were also determined. Although further studies are necessary to confirm the anticonvulsant activity of EA, our findings suggest that it may modulate seizure susceptibility in animal models.

Synthesis of Chromen-1-phenylpropen-1-one Derivatives and their Antidepressant/Anticonvulsant Activities

Background: Coumarin and chalcone are important secondary plant metabolites that exhibit a range of biological activities. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents Objective: This study aims to study new antidepressants with high biological activity and low side effects, and to provide a basis for the treatment of epilepsy and depression. Method: In this study, a series of chalcone derivatives containing a coumarin moiety (2a–2s) was designed, synthesized, and evaluated using classic antidepressant and anticonvulsant mouse models. Results: Forced swimming test results revealed that all but one of the compounds tested significantly decrease immobility time at a dose of 10 mg/kg and exhibit some antidepressant activity. Furthermore, compounds 2a, 2c, 2h, and 2k exhibit relatively high antidepressant effects in a dose-dependent manner from 10 to 30 mg/kg. Maximal electroshock seizure tests showed that compounds 2a, 2b, 2c, 2h, 2l, 2r, and 2s exhibit anticonvulsant activity at a dose of 30 mg/kg. Conclusion: Accordingly, compounds 2a, 2c, and 2h show promise as antidepressant adjunct therapy agents for treating depression in patients with epilepsy. Chromatographic neurochemical analysis of the mouse brain tissue revealed that the antidepressant effects of the compounds may be mediated by an increase in serotonin level.

PROMISING ANTI CONVULSANT EFFECT OF A HERBAL DRUG IN WISTAR ALBINO RATS

Epilepsy is one of the most common chronic disease affecting human beings.This brain disorder is characterized by tendency for recurrent seizures or fits. The seizures can leads to loss of consciousness, disturbance of movement, muscle spasms, autonomic and mental functions. In Ayurveda the epilepsy is correlated to Apasmara by classical symptomatology especially under generalized tonic-clonic seizure.Treatment of epilepsy is a long-term process and usage of conventional antiepileptic drugs Carbamazepine, Valproic acid, Ethosuximide, Phenobarbital, Benzodiazepine and Phenytoin produce unpleasant side effects in long run. So a safe herbal medicine in this condition is a necessity. The traditional healers of kerala, in their practice they widely use one herbal drug called Guchapatra (Ruta graveolens L) commonly known as Aruta in Malayalam. The plant is administered as ghrita (a preparation with ghee as the main base) for the effective management of Apasmara (Epilepsy). Guchapatra (Ruta graveolens L) is a strongly odoriferous perennial herb belonging to the family Rutaceae. The claim of anti epileptic effect of Ghee prepared with Ruta graveolens is not proven scientifically till date. The aim of present study is to test Guchapatra (Ruta graveolens .L) for its anti-convulsant effect by Maximal electroshock seizure (MES) method in Albino rats. The drug was administered in the form of Ghrita. The experiment was carried out in 3 groups having 6 Wistar albino rats per group. Phenytoin was the standard drug. Group 1 (control – distilled water), Group 2 (standard drug - Phenytoin), Group 3 (Normal dose of Guchapatra ghritam (Ghee prepared with Ruta graveolens. L). Reduction in duration of Tonic Hind Limb Extension (THE) in seconds or the complete absence of tonic extensor phase of MES convulsions was taken as the assessment criteria for Anti-convulsant effect. The observations statistically analyzed using one way ANOVA and Post Hoc Tukeys multiple comparison tests. The in-vivo experiment revealed that the Guchapatra (Ruta graveolens. L) as a ghrita (Ghee) preparation posses equal anti- convulsant effect in comparison with standard drug Phenytoin.

Pharmacological Activity of Pyrazole Derivatives as an Anticonvulsant for Benefit against Epilepsy

<b><i>Introduction:</i></b> Pediatric patients with epilepsy are prone to cognitive impairments during growth and long-term use of most antiepileptic drugs (AED). The affected children do not respond to conventional AED and may require novel drugs to manage the disease. Valproic acid, a first-line drug to treat epilepsy, is associated with serious side effects, which precludes its wider use. Thus, in the present study, we intended to develop novel substituted pyrazoles. <b><i>Methods:</i></b> The molecules were tested for anticonvulsive activity in Swiss albino mice via maximal electroshock seizure and subcutaneous pentylenetetrazole assays. The most potent molecule among the class was further assayed for its effect on behavioral and CNS depressant activity. The effect of the most potent compounds was also analyzed on various indices of oxidative stress and inflammation in mice. <b><i>Results:</i></b> The designed compounds showed significant anticonvulsive activity in mice revealing 7h as the most potent anticonvulsive agent. The most potent anticonvulsant molecule 7h further showed no behavioral alteration and considerable CNS depressant activity. It also reduces the level of oxidative stress and inflammation in the mice. <b><i>Conclusion:</i></b> Our study demonstrated utility of pyrazole derivatives as anticonvulsants against epilepsy.