Hydromethylthionine enhancement of central cholinergic signalling is blocked by rivastigmine and memantine.

Abstract

The prevention of tau protein aggregations is a therapeutic goal for the treatment of Alzheimer's disease (AD), and hydromethylthionine (HMT) (also known as leucomethylthioninium-mesylate [LMTM]), is a potent inhibitor of tau aggregation in vitro and in vivo. In two Phase 3 clinical trials in AD, HMT had greater pharmacological activity on clinical endpoints in patients not receiving approved symptomatic treatments for AD (acetylcholinesterase (AChE) inhibitors and/or memantine) despite different mechanisms of action. To investigate this drug interaction in an animal model, we used tau-transgenic L1 and wild-type NMRI mice treated with rivastigmine or memantine prior to adding HMT, and measured changes in hippocampal acetylcholine (ACh) by microdialysis. HMT given alone doubled hippocampal ACh levels in both mouse lines and increased stimulated ACh release induced by exploration of the open field or by infusion of scopolamine. Rivastigmine increased ACh release in both mouse lines, whereas memantine was more active in tau-transgenic L1 mice. Importantly, our study revealed a negative interaction between HMT and symptomatic AD drugs: the HMT effect was completely eliminated in mice that had been pre-treated with either rivastigmine or memantine. Rivastigmine was found to inhibit AChE, whereas HMT and memantine had no effects on AChE or on choline acetyltransferase (ChAT). The interactions observed in this study demonstrate that HMT enhances cholinergic activity in mouse brain by a mechanism of action unrelated to AChE inhibition. Our findings establish that the drug interaction that was first observed clinically has a neuropharmacological basis and is not restricted to animals with tau aggregation pathology. Given the importance of the cholinergic system for memory function, the potential for commonly used AD drugs to interfere with the treatment effects of disease-modifying drugs needs to be taken into account in the design of clinical trials.

• Authors: Constantin Kondak, Gernot Riedel, Charles R Harrington, Claude M Wischik, Jochen Klein
• Journal: Journal of neurochemistry (J Neurochem) Vol. 160 Issue 2 Pg. 172-184 (01 2022) ISSN: 1471-4159 [Electronic] England
• PMID: 34855998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

Chemical References

• Cholinesterase Inhibitors
• Dopamine Agents
• Acetylcholinesterase
• hydromethylthionine
• Acetylcholine
• Rivastigmine
• Methylene Blue
• Memantine

Topics

• Acetylcholine (metabolism)
• Acetylcholinesterase (metabolism)
• Animals
• Cholinesterase Inhibitors (pharmacology)
• Dopamine Agents (pharmacology)
• Drug Interactions
• Female
• Hippocampus (drug effects, metabolism)
• Memantine (pharmacology)
• Methylene Blue (analogs & derivatives, pharmacology)
• Mice
• Mice, Transgenic
• Rivastigmine (pharmacology)
• Signal Transduction (drug effects)