Comparison of the anticonvulsant potency of various diuretic drugs in the maximal electroshock-induced seizure threshold test in mice

Abstract 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.

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Salvinorin A Does Not Affect Seizure Threshold in Mice

Molecules ◽

10.3390/molecules25051204 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1204

Author(s):

Katarzyna Socała ◽

Urszula Doboszewska ◽

Piotr Wlaź

Keyword(s):

Opioid Receptor ◽

Muscular Strength ◽

Motor Coordination ◽

Clonic Seizure ◽

Seizure Threshold ◽

Salvinorin A ◽

Maximal Electroshock ◽

Threshold Test ◽

Opioid Receptor Agonist ◽

Chimney Test

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.

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Quantitative trait locus for seizure susceptibility on mouse chromosome 5 confirmed with reciprocal congenic strains

Physiological Genomics ◽

10.1152/physiolgenomics.00123.2007 ◽

2007 ◽

Vol 31 (3) ◽

pp. 458-462 ◽

Cited By ~ 14

Author(s):

Thomas N. Ferraro ◽

George G. Smith ◽

Candice L. Schwebel ◽

Falk W. Lohoff ◽

Patrick Furlong ◽

...

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Genetic Background ◽

Seizure Threshold ◽

Maximal Electroshock ◽

Seizure Susceptibility ◽

Chromosome 5 ◽

Congenic Strains ◽

Combining Data ◽

Trait Locus

Multiple quantitative trait locus (QTL) mapping studies designed to localize seizure susceptibility genes in C57BL/6 (B6, seizure resistant) and DBA/2 (D2, seizure susceptible) mice have detected a significant effect originating from midchromosome 5. To confirm the presence and refine the position of the chromosome 5 QTL for maximal electroshock seizure threshold (MEST), reciprocal congenic strains between B6 and D2 mice were created by a DNA marker-assisted backcross breeding strategy and studied with respect to changes in MEST. A genomic interval delimited by marker D5Mit75 (proximal to the acromere) and D5Mit403 (distal to the acromere) was introgressed for 10 generations. A set of chromosome 5 congenic strains produced by an independent laboratory was also studied. Comparison of MEST between congenic and control (parental genetic background) mice indicates that genes influencing this trait were captured in all strains. Thus, mice from strains having D2 alleles from chromosome 5 on a B6 genetic background exhibit significantly lower MEST compared with control littermates, whereas congenic mice harboring B6 chromosome 5 alleles on a D2 genetic background exhibit significantly higher MEST compared with control littermates. Combining data from all congenic strains, we conclude that the gene(s) underlying the chromosome 5 QTL for MEST resides in the interval between D5Mit108 (26 cM) and D5Mit278 (61 cM). Generation of interval-specific congenic strains from the primary congenic strains described here may be used to achieve high-resolution mapping of the chromosome 5 gene(s) that contributes to the large difference in seizure susceptibility between B6 and D2 mice.

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Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures

Epilepsy & Behavior ◽

10.1016/j.yebeh.2016.01.032 ◽

2016 ◽

Vol 57 ◽

pp. 95-104 ◽

Cited By ~ 11

Author(s):

Kathrin Töllner ◽

Friederike Twele ◽

Wolfgang Löscher

Keyword(s):

Surrogate Model ◽

Drug Testing ◽

Seizure Threshold ◽

Threshold Test

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Effects of propofol and thiopentone on picrotoxin convulsive threshold in the rabbit

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-092 ◽

1995 ◽

Vol 73 (6) ◽

pp. 714-717 ◽

Cited By ~ 6

Author(s):

Zyheir Hasan ◽

Said Khatib ◽

Ayman Abu-Laban

Keyword(s):

Intravenous Administration ◽

Seizure Threshold ◽

Intravenous Anesthetics ◽

Threshold Test ◽

Dose Dependent Increase ◽

Convulsive Threshold ◽

Dose Dependent ◽

Higher Doses

The purpose of the present study was to examine the effect of intravenous administration of propofol and thiopentone on picrotoxin-induced seizures using the picrotoxin convulsive threshold test in the rabbit. Neither propofol nor thiopentone at a dose of 1.25 mg/kg had any significant effect on picrotoxin seizure threshold. However, at higher doses (2.5, 5, 10 mg/kg) both propofol and thiopentone produced a significant and dose-dependent increase in the picrotoxin convulsive threshold. These findings suggest that propofol is an effective anticonvulsant against picrotoxin-induced seizures in the rabbit.Key words: convulsions, intravenous anesthetics, picrotoxin, propofol, thiopentone.

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Fluoxetine enhances maximal electroshock seizure threshold in Albino rat model when compared to phenytoin

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20175689 ◽

2017 ◽

Vol 7 (1) ◽

pp. 138 ◽

Cited By ~ 1

Author(s):

Tanmoy Gangopadhyay ◽

Ananya Mandal ◽

Uma Shanker Keshri

Keyword(s):

Seizure Threshold ◽

Albino Rats ◽

P Value ◽

Anticonvulsant Effect ◽

Maximal Electroshock ◽

Maximal Electroshock Seizure ◽

Albino Rat ◽

Co Morbidity ◽

Significant Difference ◽

Electroconvulsive Seizure

Background: Individuals with epilepsy have a higher incidence of psychiatric disorders than person without epilepsy. Epidemiological studies have shown that the co-morbidity of epilepsy and depression to be high as 50%. The conventional anti-depressants are believed to lower the seizure threshold making it difficult to treat the co-morbid depression, but animal studies have shown SSRIs, a common anti-depressant, to have anti-convulsant properties. So, we propose to study the anticonvulsant effects of fluoxetine, a SSRI, in albino rats against maximal electroshock seizure and to compare against a standard antiepileptic drug phenytoin.Methods: The anticonvulsant effect of fluoxetine was observed in model of maximal electroconvulsive seizure threshold in albino rats. The animals were divided into 3 groups having 6 animals each, receiving distilled water, fluoxetine and phenytoin respectively. The drugs were given orally, and the effect was observed on day 7, 14 and 21. Tonic hind-limb extension was taken as the parameter of electroshock seizure. The effects were compared against a standard anti-seizure drug phenytoin.Results: Fluoxetine showed significant elevation of the seizure threshold following 14 days of administration (P value 0.031). The effect was comparable to phenytoin with no significant difference after 7, 14 and 21 days of treatment (P-value 0.485, 0.699 and 0.818 respectively) though phenytoin showed significant anti-seizure effect since day 7 of treatment.Conclusions: Fluoxetine showed significant anti-seizure activity against electroconvulsive seizure in albino rats.

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OV329, a novel highly potent γ‐aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala‐kindled rats

Epilepsia ◽

10.1111/epi.17090 ◽

2021 ◽

Author(s):

Malte Feja ◽

Sebastian Meller ◽

Lillian S. Deking ◽

Edith Kaczmarek ◽

Matthew J. During ◽

...

Keyword(s):

Aminobutyric Acid ◽

Seizure Threshold ◽

Threshold Test ◽

Anticonvulsant Effects

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Discovery of novel substituted N-(6-Chloro-3-cyano-4-phenyl-4H-chromen-2-yl)-2-(4-chloro-phenoxy)-acetamide for biphasic anticancer and anticonvulsant activities

Medicinal Chemistry ◽

10.2174/1573406415666191206101617 ◽

2019 ◽

Vol 15 ◽

Cited By ~ 1

Author(s):

Divya Chauhan ◽

Syed Riaz Hashim ◽

Priyanka Rani ◽

Sushil Kumar ◽

Navratan Shrimal ◽

...

Keyword(s):

Wistar Rats ◽

Computational Study ◽

Colon Adenocarcinoma ◽

Human Colon ◽

Pharmacokinetic Profile ◽

Seizure Threshold ◽

Anticonvulsant Effect ◽

Maximal Electroshock ◽

Maximal Electroshock Seizure ◽

Ht 29

Background : Privileged 4H-chromenes possess the potent anticancer and anticonvulsant actives. By inspiring potency of 4H-chromenes and demands of present era of scaffold, discovery of effective molecule was carried out for the treatment of cancer and conversant. Objective : Designed and synthesized a novel series of 4H-chromene derivatives from one port synthesis for the treatment of cancer and conversant. Method : Substitution of side amide chain was formed in multiple steps on amine group of chromene. Later, anticancer activity of synthesized compounds was investigated against human colon adenocarcinoma cell line (HT-29) using sulforhodamine B (SRB) assay. Moreover, anticonvulsant activity was also screened out by using maximal electroshock seizure (MES) model and subcutaneous Metrazol Seizure Threshold Test (scMET) in albino Wistar rats. Neurotoxicity was evaluated using by rotarod test. Before the synthesis, docking studies were performed using various molecular targets. Subsequently, the computational study of the titled compounds was performed to predict the pharmacokinetic profile. Result: Among the fifteen tested compounds, A4 and A9 were found to be active against HT-29 cells (growth inhibitory dose 50% (GI50) <11µM). Moreover, compounds A4 showed the protection at 300mg/kg in scMET (h) for albino Wistar rats and compounds A9, A11, A15 exhibited the anticonvulsant effect at the doses 100, 300 and 300 mg/kg, respectively in MES screen(h). Conclusion : Due to these encouraging results, we concluded that both A4 and A9 may be effective against colon cancer. While compound A9 may be used as a considerable effective molecule for the treatment of epilepsy.

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