Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease.
The basic symptoms of Alzheimer's dementia, i.e., a loss in cognitive function, are due to impaired nicotinic cholinergic neurotransmission. To compensate for this impairment by drug treatment, blockers of the acetylcholine-degrading enzyme acetylcholinesterase are applied, even though this approach obviously is prone to many side-effects, including those of muscarinic nature. We have recently described a novel class of nicotinic acetylcholine receptor ligands which, similar to the action of benzodiazepines on GABA(A) receptors, allosterically potentiate submaximal nicotinic responses. The sensitizing effect is a consequence of facilitated channel opening in the presence of allosterically potentiating ligand (APL). Representative members of this class of ligands are the plant alkaloids physostigmine, galanthamine, and codeine. Because APLs could enhance nicotinic neurotransmission under conditions of reduced secretion and/or increased degradation of acetylcholine or reduced acetylcholine-sensitivity of nicotinic acetylcholine receptors, they could have a preventive and corrective action on impaired but still functioning nicotinic neurotransmission.
Maelicke
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Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, 6 Duesbergweg, D-55099, Mainz, Germany. alfred.maelicke@uni-mainz.de
Albuquerque
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D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects*; D005702:Galantamine / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007858:Learning / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*
D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D018377:Neurotransmitter Agents; D011978:Receptors, Nicotinic; D005702:Galantamine