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 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 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.

Isorhamnetin and Quercetin Derivatives as Anti-Acetylcholinesterase Principles of Marigold (Calendula officinalis) Flowers and Preparations

“…The currently available information indicates that the regulation of cholinergic neurotransmission is an effective tool for reducing the side effects caused by the expression of mnestic deficits. In this way, the prescription of acetylcholinesterase inhibitors is one of the possible pharmacological approaches for the treatment of these disorders [ 3 , 4 ].…”

Proline-Based Carbamates as Cholinesterase Inhibitors

“…ChEs belong to the group of serine hydrolases [ 19 ]. The major role of AChE is to catalyse the hydrolysis of acetylcholine (ACh) in cholinergic synapses, while BChE can hydrolyse ACh as well as other esters; nevertheless, it seems its concentration in brain is especially important at Alzheimer’s disease (AD) [ 20 , 21 ]. The inhibition of both enzymes causes an increase in the ACh concentration in cholinergic synapses and can subsequently affect a number of pathogenic processes.…”

Rapid Mechanistic Evaluation and Parameter Estimation of Putative Inhibitors in a Single-Step Progress-Curve Analysis: The Case of Horse Butyrylcholinesterase

“…This is why the step for MSF in the reaction scheme ( Figure 2 , k 16 ) is modelled as an irreversible one. It can also be stressed here that the initial rate in this curve that was obtained at a relatively high concentration (15 mM MSF) would not recognize MSF as an inhibitor, although MSF has successfully passed stage 2 of clinical trials for approval as an anti-Alzheimer’s disease drug [ 16 ].…”