Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 55, Issue 3, Pages 1285-1294Publisher
IOS PRESS
DOI: 10.3233/JAD-160733
Keywords
Acetylcholinesterase (EC 3.1.1.7); Alzheimer's disease; butyrylcholinesterase (EC 3.1.1.8); central nervous system; Lewy body; methanesulfonyl fluoride (CAS 558-25-8); Parkinson's disease
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Funding
- National Institutes of Health and Health Disparities (NIMHD), a component of the National Institutes of Health (NIH) [2G12MD007592]
- MIRDP [MH47167]
- NIMH [RR08012]
- El Paso Chapter of the Alzheimer's Association
- Coldwell Foundation of El Paso, Texas
- NATIONAL INSTITUTE OF MENTAL HEALTH [R24MH047167] Funding Source: NIH RePORTER
- National Institute on Minority Health and Health Disparities [G12MD007592] Funding Source: NIH RePORTER
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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 similar to 80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t(1/2)) of similar to 12 days. A single IM dose of 1.5 mg/kg MSF produced similar to 59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of similar to 80% inhibition in CSF AChE at the time of the injection, recovering with a t(1/2) 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.
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