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


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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Research abstracts
  Galantamine: its use in Alzheimer's
  Galantamine: in Alzheimer's patients
acetylcholinesterase inhibition
  Galantamine: therapeutic effects beyond cognition
  Galantamine: benefits to Alzheimer's patients
nicotinic receptors in Alzheimer's
  Galantamine: a study in Alzheimer's  
  Galantamine: its effects on Alzheimer's  
  Galantamine: a new treatment for Alzheimer's
  Galantamine: effect on nicotinic receptor binding
  Galantamine: an allosterically potentiating ligand
  Galantamine: nicotinic modulation in an animal model
  Galantamine: memory & nicotinic receptors in rats  
  Galantamine: a 6 month study: