title: Cholinesterase Inhibitor Therapy in Alzheimer's Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates.
abstract: Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.
authors.affiliation: Department of Psychology, University of Texas at El Paso, El Paso, TX, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Moss
authors.affiliation: Department of Biomedical Sciences, Center of Emphasis in Neurosciences, Graduate School of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University of the Health Sciences El Paso, El Paso, TX, USA.
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Perez
authors.affiliation: Department of Veterinary Pharmacology, Iwate University, Ueda, Morioka, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D007273:Injections, Intramuscular; D008252:Macaca fascicularis; D008297:Male; D018697:Nootropic Agents / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase (EC 3.1.1.7); Alzheimer’s disease; Lewy body; Parkinson’s disease; butyrylcholinesterase (EC 3.1.1.8); central nervous system; methanesulfonyl fluoride (CAS 558-25-8)