C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.

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Influence of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide on the protective action of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

Current Issues in Pharmacy and Medical Sciences ◽

10.12923/j.2084-980x/26.1/a.17 ◽

2015 ◽

Vol 26 (1) ◽

pp. 76-81

Keyword(s):

Antiepileptic Drugs ◽

Seizure Activity ◽

Protective Action ◽

Pharmacokinetic Interaction ◽

Maximal Electroshock ◽

Fluorescence Polarization Immunoassay ◽

Anticonvulsant Action ◽

Mes Test ◽

Total Brain ◽

A Current

The aim of this study was to determine the effects of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide (APIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the maximal electroshock (MES)-induced seizures in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Total brain AED concentrations were measured with fluorescence polarization immunoassay to ascertain whether any observed effects were consequent to a pharmacodynamic and/or a pharmacokinetic interaction between APIPPS and classical AEDs. Results indicate that APIPPS administered intraperitoneally at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. APIPPS at lower doses of 25, 50 and 100 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, APIPPS at 100 mg/kg significantly enhanced the anticonvulsant activity of PB and VPA, but not that of CBZ or PHT, in the MES test in mice. APIPPS at a dose of 50 mg/kg significantly potentiated the anticonvulsant action of VPA, but not that of PB in the mouse MES model. Pharmacokinetic experiment revealed that APIPPS did not alter total brain concentrations of PB or VPA in mice. Summing up, the enhanced anticonvulsant action of PB and VPA by APIPPS in the mouse MES model and lack of pharmacokinetic interactions between drugs, make the combinations of APIPPS with PB and VPA of importance for further experimental and clinical studies. The combinations of APIPPS with CBZ and PHT are neutral from a preclinical viewpoint.

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Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

Pharmacological Reports ◽

10.1007/s43440-020-00210-2 ◽

2021 ◽

Author(s):

Kinga K. Borowicz-Reutt ◽

Monika Banach ◽

Monika Rudkowska ◽

Anna Stachniuk

Keyword(s):

Antiepileptic Drugs ◽

Second Generation ◽

Antidepressant Drug ◽

Experimental Models ◽

Long Term Memory ◽

Avoidance Task ◽

Maximal Electroshock ◽

Term Memory ◽

The Brain

Abstract Background Due to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. Materials and methods As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry. Results Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. Conclusion Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

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How Antidepressant Drugs Affect the Antielectroshock Action of Antiseizure Drugs in Mice: A Critical Review

International Journal of Molecular Sciences ◽

10.3390/ijms22052521 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2521

Author(s):

Kinga K. Borowicz-Reutt

Keyword(s):

Antiepileptic Drugs ◽

Neurotrophic Factor ◽

Antidepressant Drugs ◽

Drug Effects ◽

Mechanisms Of Action ◽

Maximal Electroshock ◽

Anticonvulsant Action ◽

Mes Test ◽

Seizure Model ◽

Glial Derived Neurotrophic Factor

Depression coexists with epilepsy, worsening its course. Treatment of the two diseases enables the possibility of interactions between antidepressant and antiepileptic drugs. The aim of this review was to analyze such interactions in one animal seizure model—the maximal electroshock (MES) in mice. Although numerous antidepressants showed an anticonvulsant action, mianserin exhibited a proconvulsant effect against electroconvulsions. In most cases, antidepressants potentiated or remained ineffective in relation to the antielectroshock action of classical antiepileptic drugs. However, mianserin and trazodone reduced the action of valproate, phenytoin, and carbamazepine against the MES test. Antiseizure drug effects were potentiated by all groups of antidepressants independently of their mechanisms of action. Therefore, other factors, including brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) modulation, should be considered as the background for the effect of drug combinations.

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Effects of androsterone on the protective action of various antiepileptic drugs against maximal electroshock-induced seizures in mice

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2018.10.017 ◽

2019 ◽

Vol 101 ◽

pp. 27-34 ◽

Cited By ~ 2

Author(s):

Piotr Tutka ◽

Katarzyna Mróz ◽

Tomasz Mróz ◽

Grzegorz Buszewicz ◽

David Aebisher ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Protective Action ◽

Maximal Electroshock

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Effect of arachidonyl-2′-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the protective action of the various antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2009.09.005 ◽

2010 ◽

Vol 34 (1) ◽

pp. 18-25 ◽

Cited By ~ 25

Author(s):

Jarogniew J. Luszczki ◽

Piotr Czuczwar ◽

Anna Cioczek-Czuczwar ◽

Monika Dudra-Jastrzebska ◽

Marta Andres-Mach ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Receptor Agonist ◽

Protective Action ◽

Cb1 Receptor ◽

Maximal Electroshock ◽

Cannabinoid Cb1 Receptor ◽

Seizure Model

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Effect of N-(m-bromoanilinomethyl)-p-isopropoxyphenylsuccinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Current Issues in Pharmacy and Medical Sciences ◽

10.2478/cipms-2014-0017 ◽

2014 ◽

Vol 27 (2) ◽

pp. 76-79

Author(s):

Jarogniew J. Luszczki ◽

Ewa Marzeda ◽

Maria W. Kondrat-Wrobel ◽

Daniel Pyrka ◽

Sergey L. Kocharov ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Seizure Activity ◽

Protective Action ◽

Sine Wave ◽

Point Of View ◽

Maximal Electroshock ◽

Anticonvulsant Action ◽

Tonic Seizure ◽

Seizure Model ◽

A Current

Abstract The purpose of this study was to determine the effects of N-(m-bromoanilinomethyl)- p-isopropoxyphenylsuccinimide (BAM-IPPS - a new succinimide derivative) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the mouse maximal electroshock (MES)-induced tonic seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via ear-clip electrodes. BAM-IPPS administered (i.p.) at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). Lower doses of BAM-IPPS (50 and 100 mg/kg) had no significant impact on the threshold for electroconvulsions in mice. Moreover, BAM-IPPS (100 mg/kg) did not significantly affect the anticonvulsant potency of CBZ, PB, PHT and VPA in the mouse MES model. BAM-IPPS elevated the threshold for electroconvulsions in mice in a dosedependent manner. However, BAM-IPPS (100 mg/kg) did not affect the anticonvulsant action of various classical AEDs in the mouse MES model, making the combinations of BAM-IPPS with CBZ, PB, PHT and VPA neutral, from a preclinical point of view.

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Spironolactone potentiates the protective action of some selected antiepileptic drugs against maximal electroshock-induced seizures in mice

Annales UMCS Pharmacia ◽

10.2478/v10080-008-0167-x ◽

2009 ◽

Vol 22 (1) ◽

pp. 123-134

Author(s):

Justyna Kozińska ◽

Katarzyna M. Sawicka ◽

Anna Zadrożniak ◽

Ewa Wojda ◽

Marta Andres-Mach ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Protective Action ◽

Maximal Electroshock

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Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice

Pharmacology Biochemistry and Behavior ◽

10.1016/j.pbb.2011.01.002 ◽

2011 ◽

Vol 98 (2) ◽

pp. 261-267 ◽

Cited By ~ 33

Author(s):

Jarogniew J. Luszczki ◽

Marta Misiuta-Krzesinska ◽

Magdalena Florek ◽

Piotr Tutka ◽

Stanislaw J. Czuczwar

Keyword(s):

Antiepileptic Drugs ◽

Protective Action ◽

Synthetic Cannabinoid ◽

Maximal Electroshock

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Screening of Some Novel 4, 5 Disubstituted 1, 2, 4-Triazole-3-thiones for Anticonvulsant Activity

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666191209103003 ◽

2020 ◽

Vol 20 (1) ◽

pp. 41-48 ◽

Cited By ~ 1

Author(s):

Krishan K. Verma ◽

Umesh K. Singh ◽

Jainendra Jain

Keyword(s):

Drug Administration ◽

Anticonvulsant Activity ◽

Motor Coordination ◽

Docking Study ◽

Maximal Electroshock ◽

Gamma Amino Butyric Acid ◽

Molecular Docking Study ◽

Amino Butyric Acid ◽

Mes Test ◽

Autodock 4.2

Objective: In the present study, we synthesized fifteen 4, 5-disubstituted 1, 2, 4-triazol- 3-thione derivatives and evaluated for anticonvulsant activity with neurotoxicity determination. Method: The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The molecular docking study was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. The anticonvulsant activity was assessed by maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) tests. The neurotoxicity was assessed by rotarod ataxia test. Results: In MES test, compounds 5a, 8a and 9a were found active at 100 mg/kg and five compounds were found active at 300 mg/kg dose after 1 hr of administration. After 4 hr of drug administration, only two compounds 8a and 9a exhibited protection at 100 mg/kg. In scPTZ test, three compounds 2a, 6a and 8a were found active at 100 mg/kg and 7a was active at 300 mg/kg after 1 hr of test drug administration. Most of the compounds were found active in MES test with 8a and 9a being the most active among all. In docking study, 2a was found to be best compound based on the binding energy of -6.5 kcal/mol and estimated inhibition constant of 17.2 µM. Conclusion: Majority of synthesized compounds were found active in MES test, whereas only few were found to possess anti scPTZ activity. Among all compounds, only 14a caused motor coordination impairment in rotarod ataxia test at 300 mg/kg 1 hr duration.

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