CONVULSANT HYDRAZIDES II: COMPARISON OF ELECTRICAL CHANGES AND ENZYME INHIBITION INDUCED BY THE ADMINISTRATION OF THIOSEMICARBAZIDE

¹ Department of Pharmacology, University of Illinois, School of Medicine, Chicago, Illinois

Progressive enzymatic inhibition in the l-glutamic acid decarboxylase system has been shown to parallel progressive stages of developing electrical seizure activity in isolated cortical, normal cortical and subcortical tissues following administration of thiosemicarbazide.

At all stages additions of coenzyme increased enzyme activity indicating that apoenzyme had not been destroyed. Concurrent measurements of the synthesis of pyridoxal phosphate indicated that coenzyme production was not altered by thiosemicarbazide.

It was suggested, therefore, that the mode of action of thiosemicarbazide in producing seizures is by blockade of the coenzyme, possibly through formation of an inert complex.

Parallel studies of electrical and enzymatic activity indicated that seizures are not precipitated by the drug. Thiosemicarbazide appears rather to set up conditions of instability through enzymatic inhibition, and spontaneous electrical activity then triggers the convulsions.

Subcortical structures showed slightly higher endogenous l-glutamic acid decarboxylase activity and greatest unsaturation of the apoenzyme. These factors are considered to contribute to the preferential action of thiosemicarbazide observed at subcortical sites.