Allosteric modulation of nicotinic receptors as a treatment
strategy for Alzheimer's disease.
Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and
Pathobiochemistry, Johannes Gutenberg University Medical School, Mainz, Germany.
Dement Geriatr Cogn Disord 2000
Sep;11 Suppl 1:11-8
Impairment of the central cholinergic system has a pivotal role in the cognitive
decline observed in patients with Alzheimer's disease (AD). One of the most
prominent cholinergic deficits is the reduced number of nicotinic acetylcholine
receptors (nAChR) in the brain. Since these receptors are important for memory
and learning, enhancing nicotinic neurotransmission is a promising treatment
strategy for AD. The two most common approaches to correcting these cholinergic
deficits are to increase the synaptic availability of acetylcholine (ACh) by
inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh
(nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies
suggest that AChE inhibitors produce only short-term symptomatic improvement.
Similarly, long-term use of nicotinic agonists may induce desensitization of
nicotinic receptors, leading to tolerance and therefore limiting the duration of
efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents
the development of tolerance. Allosteric modulators bind to a site on nAChR that
is different to the binding site of the natural agonist, ACh. This allosteric
interaction amplifies the actions of ACh at post- and presynaptic nAChR. In
particular, presynaptic nAChR are capable of modulating the release of ACh and
other neurotransmitters, such as glutamate, serotonin and GABA, which may
contribute to symptoms of the illness. Allosteric modulation of nAChR could
therefore produce significant therapeutic benefit in AD. One of the most potent
of these allosteric modulators is galantamine. As well as modulating nAChR,
galantamine inhib- its AChE. The extent to which the clinical benefits of
galantamine are attributable specifically to its nicotinic effects is uncertain
and requires further investigation. However, galantamine maintains patients'
level of cognitive and daily function for at least 1 year, which has not been
reported for other AChE inhibitors. Galantamine's modulatory effects on nAChR
may influence transcriptional regulation, resulting in an increased synthesis of
nAChR. This may account for galantamine's sustained efficacy.