Intraperitoneal administration of 340 kDa human plasma butyrylcholinesterase increases the level of the enzyme in the cerebrospinal fluid of rats

Abstract

Human butyrylcholinesterase (BuChE) is being developed as a new therapeutic for protection against the toxicity of organophosphorus agents and cocaine. The purified BuChE consists predominantly of 340 kDa tetramers and contains less than 5% monomers and dimers. Our goal was to determine whether BuChE crosses the blood–cerebrospinal fluid (CSF) barrier. Rats were injected intraperitoneally with 1 mg of purified human BuChE. Plasma BuChE activity increased nearly 400-fold, while BuChE activity in the CSF increased three-fold. Sucrose density centrifugation showed that the human BuChE molecule in the rat CSF was a tetramer. Immunoprecipitation confirmed the identity of the CSF BuChE as human BuChE. The lower amount of human BuChE in the CSF (0.04%) than of smaller proteins (0.1–1%), with respect to their levels in plasma, supports the idea that passage through the blood–CSF barrier depends on molecular size. BuChE in the CSF could serve to protect the brain from the neurotoxicity of organophosphorus pesticides and cocaine.