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

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

Advances in Clinical and Experimental Medicine ◽

10.17219/acem/68694 ◽

2018 ◽

Vol 27 (5) ◽

pp. 609-613 ◽

Cited By ~ 3

Author(s):

Katarzyna Załuska ◽

Maria Kondrat-Wróbel ◽

Jarogniew Łuszczki

Keyword(s):

Seizure Threshold ◽

Maximal Electroshock ◽

Threshold Test ◽

Diuretic Drugs

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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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Influence of aminophylline on the anticonvulsive action of gabapentin in the mouse maximal electroshock seizure threshold model

Journal of Neural Transmission ◽

10.1007/s00702-007-0795-4 ◽

2007 ◽

Vol 114 (12) ◽

pp. 1539-1545 ◽

Cited By ~ 7

Author(s):

J. J. Luszczki ◽

K. Jankiewicz ◽

M. Jankiewicz ◽

S. J. Czuczwar

Keyword(s):

Threshold Model ◽

Seizure Threshold ◽

Maximal Electroshock ◽

Maximal Electroshock Seizure ◽

Anticonvulsive Action ◽

Electroshock Seizure Threshold

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Synthesis and Anticonvulsant Activity of α-Amino Acid Amide Derivatives

Current Bioactive Compounds ◽

10.2174/1573407214666180530081328 ◽

2019 ◽

Vol 15 (5) ◽

pp. 547-561

Author(s):

Valerie Currier ◽

Maryam Molki ◽

Katelyn Fryman ◽

Lacey D. Rodgers ◽

A. Michael Crider

Keyword(s):

Amino Acid ◽

Side Effects ◽

Anticonvulsant Activity ◽

Acid Amide ◽

New Drugs ◽

Seizure Threshold ◽

Maximal Electroshock ◽

Maximal Electroshock Seizure ◽

Maximal Electroshock Seizure Test ◽

Amide Derivatives

Background: Epilepsy is a disease of the central nervous system that affects approximately 50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years, almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action and minimal side effects. Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard battery of anticonvulsant tests. Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α- carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower seizure threshold when evaluated in the intravenous metrazol seizure test. Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in complex partial seizures.

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Design, synthesis and anticonvulsant-analgesic activity of new N-[(phenoxy)alkyl]- and N-[(phenoxy)ethoxyethyl]aminoalkanols

MedChemComm ◽

10.1039/c6md00537c ◽

2017 ◽

Vol 8 (1) ◽

pp. 220-238 ◽

Cited By ~ 6

Author(s):

Anna Rapacz ◽

Anna M. Waszkielewicz ◽

Katarzyna Pańczyk ◽

Karolina Pytka ◽

Paulina Koczurkiewicz ◽

...

Keyword(s):

Analgesic Activity ◽

Anticonvulsant Activity ◽

Seizure Threshold ◽

Maximal Electroshock ◽

Maximal Electroshock Seizure ◽

Design Synthesis ◽

Electroshock Seizure Threshold

New aminoalkanols have been synthesized and evaluated for their anticonvulsant activity in maximal electroshock (MES), maximal electroshock seizure threshold (MEST) and pentylenetetrazol (PTZ) tests, and show promising activity.

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