Anticonvulsant activity of new 3- and 4-benzoilpiridines oxime derivatives in comparison with valproic acid

Abstract

The aim of the research was to study the wide range of anticonvulsant effects of new 3- and 4-benzoylpyridines oxime derivatives in comparison with the reference drug valproic acid, it included assessment of motor and EEG convulsive state manifestations and epileptic status. To identify the most effective compound we studied the anticonvulsant effects in the models of generalized convulsions caused by maximal electroshock seizure test and subcutaneous administration of pentylenetetrazole. Later, the most active compound was studied in the models of chronic cobalt-induced epilepsy and epileptic status caused by neurotoxin d, l-homocysteine thiolactone. The original compounds prevent convulsions and protect 100% of animals against death in a dose-dependent manner in the maximal electroshock seizure test with superiority over valproic acid. In the pentylenetetrazole epilepsy model the compounds decrease the latent period of the first clonic seizure onset. The leader compound GIZH-298 (60 mg/kg) has a pronounced anticonvulsant effect on primary and, especially, on secondary epileptic foci in the cobalt-induced epilepsy model that generates seizure activity in various brain structures with a predominant effect in the cortex and hypothalamus. GIZH-298 (60 mg/kg, 50 min after administration) completely eliminates the secondary-generalized tonic-clonic seizures (SGTCS) and protects 100% of animals against death in the stable stage of the epileptic status caused by the administration of d, l-homocysteine thiolactone. Valproic acid (100 mg/kg) does not fully eliminate the SGTCS and protects against death only 71% of animals. 3- and 4-benzoylpyridine oxime derivatives have pronounced anticonvulsant activity with superiority over valproic acid.