Affiliations: [a] Institute of Experimental and Clinical Pharmacology and Toxicology, Laboratory of Neuropharmacology, University of Freiburg, Freiburg, Germany | [b] Department of Neurosurgery, Neurocenter, Freiburg, Germany
Correspondence:
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Corresponding author: Dr. Rolf Jackisch, Institute of Experimental & Clinical Pharmacology & Toxicology, Laboratory of Neuropharmacology, University of Freiburg, Hansastrasse 9A, D-79104 Freiburg, Germany. Tel.: + 49 761 203 9545; Fax: +49 761 203 9500; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Note: [2] present address: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
Note: [] Communicated by Marcella Reale
Abstract: Fresh specimens of human and rat neocortex were used to determine direct and indirect inhibitory potencies of choline esterase inhibitors (ChEIs) on ChE and the release of acetylcholine (ACh), respectively. Km values of ChE in homogenates of rat and human neocortex did not differ significantly, whereas the specific activity of ChE was > times higher in the rat. Butyryl ChE exhibited a higher Km and a lower specific activity than ACh esterase in human neocortex. Inhibition of ChE in rat and human tissue was similar [IC50 (nM; human): donepezil: 14, physostigmine: 22, tacrine: 95, galanthamine: 575, rivastigmine: 9120]. In neocortex slices preincubated with [3H]choline, the electrically evoked release of [3H]ACh was inhibited up to 60% by ChEIs (IC50 (nM, rat): donepezil: 30, physostigmine: 39, tacrine: 302, galanthamine: 646, rivastigmine: >10000). Similar IC50-values were also estimated for ACh release in human neocortex, although the maximal inhibitory effects were much smaller (∼20%). We conclude that in comparison to rats: 1) neocortical ChE concentrations are lower and 2) that ChEIs have weaker indirect (muscarine receptor-mediated) presynaptic inhibitory effects in the human brain. We further suggest that a combination of ChEIs with brain-selective muscarine autoreceptor antagonists might help to improve their clinical efficacy.
