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Allosterically
potentiating ligands of nicotinic receptors as a treatment strategy for
Alzheimer's disease.
Maelicke A, Schrattenholz A, Samochocki M, Radina M, Albuquerque
EX.
Laboratory of Molecular Neurobiology,
Institute of Physiological
Chemistry and Pathobiochemistry,
Johannes-Gutenberg University Medical School,
Mainz, Germany.
Behav Brain Res 2000 Aug;113(1-2):199-206
ABSTRACT
One of the most prominent
cholinergic deficit in Alzheimer's disease (AD) is the reduced number of
nicotinic acetylcholine receptors (nAChR) in the hippocampus and cortex of AD
patients, as compared to age-matched controls. This deficit results in reduced
nicotinic cholinergic excitation which may not only impair postsynaptic
depolarization but also presynaptic neurotransmitter release and Ca2+-dependent
intracellular signaling, including transcriptional activity. Presently, the most
common approach to correct the nicotinic cholinergic deficit in AD is the
application of cholinesterase inhibitors. Due to the resulting increase in
synaptic acetylcholine levels, both in concentration and time, additional nAChR
molecules, e.g. those more distant from the ACh release sites, could be
activated. As an obvious disadvantage, this approach affects cholinergic
neurotransmission as a whole, including muscarinic neurotransmission. As a novel
and alternative approach, a treatment strategy which exclusively targets
nicotinic receptors is suggested. The strategy is based on a group of modulating
ligands of nicotinic receptors, named allosterically potentiating ligands (APL),
which increase the probability of channel opening induced by ACh and nicotinic
agonists, and in addition decrease receptor desensitization. The action of APL
on nicotinic receptors is reminiscent of that of benzodiazepines on GABA(A)
receptors and of that of glycine on the NMDA-subtype of glutamate receptor.
Representative nicotinic APL are the plant alkaloids physostigmine, galanthamine
and codeine, and the neurotransmitter serotonin (5HT). The potentiating effect
of APL on nicotinic neurotransmission has been shown by whole-cell patch-clamp
studies in natural murine and human neurons, and in murine and human cell lines
expressing various subtypes of neuronal nAChR.
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