Are Two Cholinesterase Inhibitors Better Than One?

Summarized by Robert W. Griffith, MD
July 26, 2002 (Reviewed: April 16, 2004)

introduction

"Cholinesterase inhibitors" are a class of drugs that have been used for a number of years to slow the progression of Alzheimer's disease. The idea behind them is as follows: In Alzheimer's, there is a lack of a substance called acetylcholine in the neighborhood of the cells in the brain that show degenerative changes. Acetylcholine is a neurotransmitter, that is to say it helps transmit signals from one nerve cell to another. Acetylcholine is normally removed by enzymes called cholinesterases, which split it up so that it is inactivated. A drug that inhibits cholinesterase means that more acetylcholine is available to carry out nerve cell communications.

The cholinesterases

So far, acetyl cholinesterase (AChE) inhibitors are the main drugs of this class used in Alzheimer's. However, scientists have shown that there are in fact two sorts of cholinesterase, either of which can be inhibited by appropriate drugs.

The second cholinesterase is butyryl cholinesterase (BuChE). It's very similar to AChE, but there are some small molecular differences. If acetylcholine comes in contact with either AChE or BuChE, it is split up and its function as a transmitter of nerve signals is destroyed.

AChE is the main enzyme involved in the breakdown of acetylcholine in normal brains. However, it now seems that BuChE may have an important part to play in brains with degenerative changes. Why is this? As Alzheimer's disease progresses, AChE activity decreases in some brain areas, while BuChE activity in these areas increases. The increase in BuChE is greater in areas of the brain associated with learning, memory, behavior, and emotional responses.

Amyloid deposits, or plaques

Pathologists have shown that Alzheimer's disease is characterized by deposition of a protein substance called amyloid and by the formation of tangles of nerve cell filaments in the affected areas of the brain. Recently it has been found that some of these amyloid deposits, which are laid out in plaques, are really harmless, being seen in elderly people without any loss of mental abilities. It's important to know what factors might cause these "benign" plaques to be transformed into plaques that cause degenerative damage. BuChE is one such possible factor. Advanced amyloid plaques in Alzheimer's brains have very high BuChE reactivity, whereas this is low in the early, benign deposits.

Workers at the US National Institutes of Health (NIH) are developing drugs that inhibit BuChE exclusively. The effects of some of them have been studied in elderly rats in learning mazes. The rats learned better with very low doses of the BuChE-selective inhibitors - much lower doses than those needed for AChE-selective inhibitors to produce similar effects. Moreover, the BuChE inhibitors didn't cause the typical side effects seen with AChE inhibitors.

Clinical findings

Of the three commonly prescribed AChE inhibitors - donepezil, galantamine, and rivastigmine - the first two are selective AChE inhibitors, while rivastigmine inhibits both AChE and BuChE. When Alzheimer's patients are given rivastigmine it's possible to show rapid and long-lasting inhibition of both AChE and BuChE levels in the spinal fluid.

What's are we to make of this? The clinical benefits of rivastigmine in Alzheimer's disease are, at first sight, very similar with those of the other major AChE inhibitors, and all three have similar side effects. So it will be necessary to compare rivastigmine with one or other of the other AChE-specific inhibitors in a head-to-head study, to see if the additional BuChE inhibition with rivastigmine produces relevant differences in the clinical effects -- good or bad.

Cholinesterase inhibitors are helpful in Alzheimer's disease, but there are certainly better drugs on the horizon. The author of this review, Dr Ballard, thinks that AChE inhibition is more important in the early stages of Alzheimer's; however, as the disease progresses, BuChE inhibition is needed to help restore acetylcholine levels. Doubtless, clinical studies with new BuChE inhibitors will clarify this, and contribute to our knowledge of the development of Alzheimer's disease.

Source

• Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition. CG. Ballard, Eur Neurol , 2002, vol. 47, pp. 64--70

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