Cholinesterase Inhibitors and Beyond
Pp. 187-213 (27)
Giancarlo Pepeu and Maria G. Giovannini
Cholinesterase inhibitors (ChEIs) were introduced in the therapy of
Alzheimer Disease (AD) in the nineties with great expectations. The hopes and large
interest raised by these drugs are well demonstrated by 12,000 references listed by
PubMed under ChEI for 1995-2007. The list is reduced to 2500 if we confine ourselves
to ChEIs and dementia. Of them about 500 were published in the last two years.
Whereas an increase in brain acetylcholine and an improvement of cognitive deficits
have been consistently demonstrated in animal models of AD, from aging rats to
transgenic mice, ChEIs clinical effectiveness has been and is still a matter of contrasting
opinions. These range from the negative conclusions of the AD2000 trial on donepezil,
claiming that it is no cost effective, with benefits below minimally relevant threshold, to
the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are
efficacious for mild to moderate AD, irrespective of their different selectivity for AChE
and BuChE. The possibility that ChEIs may exert their effects through mechanisms
beyond cholinesterase inhibition has been envisaged. However, according to the
information presented in this review, the “classical” ChEIs, donepezil, rivastigmine and
galantamine, show no pharmacological actions beyond cholinesterase inhibition which
may play an important role in their therapeutic efficacy. The diverging opinions on
clinical efficacy do not discourage from developing new ChEIs, and the so called
multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but
other indications for these drugs may be considered, including vascular dementia, mild
cognitive impairment, and the ethically sensitive improvement of memory and learning
in healthy subjects.
An update of this review carried out four years after its first publication reveals a
persistent interest for ChEIs, as demonstrated by the publication of more than 3500
preclinical and clinical papers since 2010. However, no substantial development in the
field has come about, namely no novel ChEI effects have been detected beside those
caused by inhibition of cholinesterases and the ensuing acetylcholine increase. The only
novel indication is the extension of rivastigmine to the treatment of dementia with Lewy
bodies and Parkinson’ disease dementia, in some countries.
Acetylcholine, acetylcholinesterase, alzheimer therapy, β-Amyloid,
novel cholinesterase inhibitors.
Department of Pharmacology, Viale Pieraccini 6, 50139 Florence, Italy.