THE CEREBRAL DISTRIBUTIONS OF A TERTIARY AND A QUATERNARY ANTICHOLINESTERASE AGENT FOLLOWING INTRAVENOUS AND INTRAVENTRICULAR INJECTION

¹ Department of Physiology and Pharmacology, Graduate School of Medicine, University of Pennsylvania, Philadelphia, and Campbell Pharmaceutical Company, Research Laboratories, New York, New York

Following the intravenous administration to rabbits of the approximate LD₅₀'s of 2-diethoxyphosphinylthioethyldimethylamine acid oxalate (217-AO; 0.32 micromol./kgm.) and the corresponding methiodide (217-MI; 0.087 micromol./kgm.), the tertiary compound produced 90 per cent inactivation of the total brain acetyicholinesterase (AChE), whereas the quaternary derivative caused no measurable inhibition. When the same dose of the latter was injected via a common carotid artery, slight inhibition of brain AChE resulted. However, marked apparent inactivation of the AChE of the whole brain followed the injection of one-tenth or one-hundredth this dose of 217-MI into a lateral ventricle. Thus, the blood-brain barrier limits the passage of the quaternary agent from the circulation to the cerebral AChE. Assay of the brain-halves separately following intraventricular injection of 217-MI showed that the agent wss fairly equally distributed between the two halves after three to four hours. The degree of inhibition of erythrocytic AChE at that time indicated that most of the 217-MI had passed into the circulation. However, traces of the free compound remained in the cerebrospinal fluid of some animals up to the second day after injection. From determinations of the AChE activities of the right brain-halves and of mixtures of the left halves with control homogenate, it was found that significant amounts of free 217-MI remained within the cerebral tissue of most animals, probably at intracellular sites, as long as four days after intraventricular injection. Calculation of the cerebral AChE activities in vivo from the same figures indicated that the enzyme was regenerated at approximately the same rate as that which followed inhibition by the intravenous injection of 217-AO. Two mechanisms are suggested for the regeneration of AChE in the presence of free, intracellular 217-MI: hydrolytic reactivation of enzyme external to the neuronal membranes, and synthesis of AChE within the endoplasmic reticulum.

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