Study of the anticonvulsant activity of the original valproic acid amino ester in various models of convulsive syndrome

Introduction. Despite a significant number of antidotes (atropine, pyridoxine) and anti-seizure drugs in clinical practice (benzodiazepines, barbiturates, valproates, anesthetics), the development of new antidotes for the relief of refractory seizures and recurrence of convulsive syndrome is actual problem.

The aim of the work was to study the specific pharmacological activity of a new original derivative of valproic acid in an experiment on models of convulsive syndrome with different mechanisms of action.

Material and methods. A comparative study of the effectiveness of the original substance ((1-methylpiperidin-4-yl)-2-propylpentanoate hydrochloride, VAA) was carried out on electroshock, GABA-lytic, catecholamine-dependent seizure models in rats and mice.

Results. A significant decrease in seizure activity was revealed in the group with prophylactic administration of VAA in the dose range of 11, 27 and 65 mg/kg in comparison with the control group received only phenylcarbamate. In an intergroup comparison, a low dose (11 mg/kg) more than others had an effect on the latent period of the onset of phenylcarbamate seizures, an average dose (27 mg/kg) reduced the duration of the seizure period, a high dose (65 mg/kg) affected the severity of convulsions, while the integral indicator (convulsive activity) did not differ between the medium and high dose subgroups. There was no significant decrease in seizure activity in models with the use of corazol, camphor, and the model of maximum electric shock.

Limitations. Testing of new pharmaceutical substances (study of efficacy and safety) should be carried out on laboratory animals before confirmation of efficacy in humans. The quantity of animals was limited by the need to comply with bioethical principles and sufficient number for statistically significant results and amounted 6 individuals in each group.

Conclusion. The release of valproic acid during the metabolism of VAA is slow and its concentration is insufficient to realize the universal anticonvulsant activity of VAA. It is necessary to further study the effect on cognitive functions and neuroprotective properties. Since antidote efficacy superior to atropine has been previously demonstrated, VAA is recommended for development as an antidote for organophosphorus poisoning.

Compliance with ethical standards. The experiment with animals was approved by the bioethical commission of the Golikov Research Center of Toxicology.

Author contributions:
Melekhova A.S. — conducting scientific research (experiments on animals), material processing, text writing;
Melnikova M.V., Belskaya A.V., Bondarenko A.A. — conducting scientific research (experiments on animals);
Bespalov A.Ya. — development and synthesis of vlproic acid amino ester for experiments;
Zorina V.N. — material processing, text writing;
Shustov E.B. — scientific guidance during research, text editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Conflict of interests. The authors declare no conflict of interest.

Funding. The work was carried out according to the research plan within the framework of a state assignment.

Received: June 22, 2023 / Accepted: October 19, 2023 / Published: October 30, 2023