Inhibition of 4-aminopyridine-induced seizures in mice by a novel 3-substituted 1,4-benzodiazepine

Keywords: propoxazepam, 4-aminopyridine, anticonvulsive action, potassium channels

Abstract

Some of highly effective antiepileptic substances share the polymodal pharmacological action which determines the possibility of their use for treatment of pathogenetically similar diseases. Inhibitory mediator systems influence for example, suggests the combination in the pharmacological spectrum such actions as antiepileptic, analgesic (antineuropathic) and other actions.

The aim of the study was evaluation of anticonvulsant effect of 7-bromo-5-(o-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one (propoxazepam) on the model of 4-aminopyridine (4-AP) – induced myoclonic seizures and characterization of its possible participation in modulation of the function of voltage-dependent potassium channels.

4-AP (10.3 mg/kg, subcutaneously) was administered 30 minutes after intraperitoneal administration of propoxazepam different doses (20, 28, 40, 60 and 80 mg/kg) and the time and quantity of myoclonic and tonic convulsions as well as total time to the lethal effect were evaluated.

It was found that in this model, propoxazepam possess moderate activity (ED50 = 37,3 ± 7.9 mg/kg) Even at high doses (80 mg/kg) of the test compound, anticonvulsive action did not reach 100%. The quantity of myoclonic seizures and the latency time of their onset have no statistically significant differences in comparison with the data of animals of the control group. On the contrary, the number (and percentage representation) of tonic convulsions in the common seizure episode increased, which is due to the possible inhibitory effect of propoxazepam, which is carried out primarily through GABA-ergic mechanisms.

References

1. Jefferys J. Advances in understanding basic mechanisms of epilepsy and seizures // Seizure. – 2010. – N 19. – P. 638–646.
2. Jong M. Rho, Raman Sankar. Progress in epilepsy. Research the pharmacologic basis of antiepileptic drug action // Epilepsia. – 1999. – N 40. – P. 1471–1483.
3. Golovenko M. Ya., Larionov V. B., Reder A. S., Valivodz I. P., Mykhailova T. V. Antagonism of GABAA-receptor complex allosteric modulators – propoxazepam and bemegridee, possessing affinity to different macromolecule subunits // Med. clin. chemistry. – 2018. – V. 20, N 2. – P. 18–26.
4. Golovenko N. Ya., Larionov V. B., Reder A. S., and. Valivodz’ I. P. An еffector analysis of the interaction of propoxazepam with antagonists of GABA and glycine receptors // Neurochem. J. – 2017. – V. 11, N 4. – Р. 302–308.
5. Larionov V. B., Reder A. S., Golovenko N. Ya., Valivodz` I. P. Propoxazepam antiepileptic efficacy on the maximal electroshock model // Pharmacol. Drug Toxicol. – 2017. – N 53. – P. 47–53.
6. Golovenko M. Ya., Reder A. S., Larionov V. B., Balivodz` I. P. Propoxazepam influence on thiosemicarbazide-induced GABA-deficient seizures development in mice // Clin. Pharmacy. – 2017. – V. 21, N 2. – Р. 34–40.
7 Golovenko N. Ya., Larionov V. B., Andronati S. A., Valivodz` I. P., Yurpalova T. A. Рharmacodynamic analysis of propoxazepam interaction with GABA-benzodiazepine-receptor-ionophore complex // Neurophysiol. – 2018. – N 50. – Р. 2–10.
8. Larionov V., Golovenko N., Reder S., Valivodz` I. Propoxazepam conformation and its orientation in the GABAA-receptor binding site // Ukr. Biopharmac. J. – 2018. – N 54. – P. 10–17.
9. Urbach V. U. Statistical analysis in biological and medical research. – M.: Medicine, 1975. – 297 p.
10. Medina-Ceja L., Morales-Villagraґn A., Tapia R. Action of 4-aminopyridine on extracellular amino acids in hippocampus and entorhinal cortex: a dual microdialysis and electroencephalographic study in awake rats // Brain Res. Bull. – 2000. – V. 53. – P. 255–262.
11. Yamaguchi S., Rogawski M. A. Effects of anticonvulsant drugs on 4-aminopyridine-induced excretion in mice // Epilepsy Res. – 1992. – N 11. – P. 9–16.
Published
2019-02-12
How to Cite
Golovenko, N. Y., Larionov, V. B., REDER, A. S., & Valivodz’, I. P. (2019). Inhibition of 4-aminopyridine-induced seizures in mice by a novel 3-substituted 1,4-benzodiazepine. Farmatsevtychnyi Zhurnal, (5-6), 90-96. https://doi.org/10.32352/0367-3057.5-6.18.7