Effects of chronic metrifonate treatment on cholinergic enzymes and the blood-brain barrier

After an acute (4 h) treatment with an irreversible cholinesterase inhibito r organophosphate, metrifonale (100 mg/kg i.p.), the activities of both ace tyl- and butyrylcholinesterase were inhibited (66.0-70.7% of the control le vel) in the rat brain cortex and hippocampus. There were no significant cha nges in the acetyl- and butyrylcholinesterase activities in the olfactory b ulb, or in the choline acetyltransferase activity in all three brain areas. After chronic (2 or 5 week) metrifonate treatment (100 mg/kg daily i.p.), the activities of both cholinesterases were substantially inhibited in the rat brain cortex and hippocampus (15.8-31.8% of the central levels), but th ere was no inhibition of the choline acetyltransferase activity. Moreover, chronic metrifonate treatment did not have any effect on the distribution o f the acetylcholinesterase molecular forms. In vitro, metrifonate proved to be a more potent inhibitor of butyryl- than of acetylcholinesterase in bot h the cortex and the hippocampus. In the hippocampus, the butyrylcholineste rase activity was twice as sensitive to metrifonate inhibition as that in t he cortex (IC50 values 0.22 and 0.46 muM, respectively). The effects of chr onic (5 week) metrifonate treatment on the blood-brain barrier of the adult rat were examined. The damage to the blood-brain barrier was judged by the extravasation of Evans' blue dye in three brain regions: the cerebral cort ex, the hippocampus, and the striatum. No extravasation of Evans' blue dye was found in the brain by fluorometric quantitation. These data indicate th at chronic metrifonate treatment may increase the extracellular acetylcholi ne level via cholinesterase inhibition, but it does not have any effects on the blood-brain barrier. Therefore, it appears reasonable to hypothesize t hat cholinesterase activities do not play a role in the blood-brain barrier permeability. (C) 2001 Elsevier Science Ltd. All rights reserved.