Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer's disease

One of the most prominent cholinergic deficit in Alzheimer's disease (AD) i s the reduced number of nicotinic acetylcholine receptors (nAChR) in the hi ppocampus and cortex of AD patients, as compared to age-matched controls. T his deficit results in reduced nicotinic cholinergic excitation which may n ot only impair postsynaptic depolarization but also presynaptic neurotransm itter release and Ca2+-dependent intracellular signaling, including transcr iptional activity. Presently, the most common approach to correct the nicot inic cholinergic deficit in AD is the application of cholinesterase inhibit ors. Due to the resulting increase in synaptic acetylcholine levels, both i n concentration and time, additional nAChR molecules, e.g. those more dista nt from the ACh release sites, could be activated. As an obvious disadvanta ge, this approach affects cholinergic neurotransmission as a whole, includi ng muscarinic neurotransmission. As a novel and alternative approach, a tre atment strategy which exclusively targets nicotinic receptors is suggested. The strategy is based on a group of modulating ligands of nicotinic recept ors, named allosterically potentiating ligands (APL), which increase the pr obability of channel opening induced by ACh and nicotinic agonists, and in addition decrease receptor desensitization. The action of APL on nicotinic receptors is reminescent of that of benzodiazepines on GABA, receptors and of that of glycine on the NMDA-subtype of glutamate receptor. Representativ e nicotinic APL are the plant alkaloids physostigmine, galanthamine and cod eine, 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. (C) 2000 Elsevier Scie nce B.V, All rights reserved.