Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine

Summary: Galanthamine, physostigmine and 9-amino-l,2,3,4-tetrahydroacridine (tacrine) were evaluated sinhibitors of human acetylcholinesterase activity from samples of postmortem human brain, fresh brain cortexbiopsies and human erythrocytes. Acetylcholinesterase activity was most effectively inhibited in all tissues byphysostigmine, followed by tacrine and galanthamine. The respective inhibitor concentrations exerting a halfmaximal effect (IC 50 ) on acetylcholinesterase in postmortem human brain frontal cortex were 14nmol/l,1.0 μιηοΐ/ΐ and 3.2 μηιόΐ/ΐ versus 15 nmol/1, 1.1 μτηοΐ/ΐ and 2.8 μιηοΐ/ΐ in the hippocampus region. In addition,the Inhibition of acetylcholinesterase by galanthamine was similar in postmortem brain and brain corticalbiopsies from patients submitted to brain-tumour removal, indicating that postmortem changes up to 28 hafter death probably did not influence the measurement of acetylcholinesterase Inhibition. While physostigmineand tacrine acted equally on acetylcholinesterase from different sources, galanthamine was 10-fold less potentin inhibiting the enzyme activity from human brain than from human erythrocytes. Comparison with issuesfrom mice revealed that galanthamine was selectively more potent in suppressing acetylcholinesterase in humanerythrocytes. The results are discussed in the light of pharmacokinetic data, and conclusions are drawn forfurther clinical studies.in