Modulation of nicotinic receptor activity in the central nervous system: Anovel approach to the treatment of Alzheimer disease

Impaired cholinergic function in the central nervous system is an early fea ture of Alzheimer disease (AD). Currently, cholinergic deficit is usually c orrected by increasing the amount of acetylcholine in the synapse by inhibi ting acetylcholinesterase (AChE). One of the most consistent cholinergic de ficits in AD is the reduced expression of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are essential for learning and memory, restoring nicotinic cholinergic function is a promising approach t o treating AD. Allosteric modulation of nAChR is a novel approach, which ci rcumvents development of tolerance through long-term use of conventional ni cotinic agonists. Allosteric modulators interact with receptor-binding site s distinct from those capable of recognizing the natural agonist. Positive allosteric modulation of nAChR activity has no effect on conductance of sin gle channels; instead, by facilitating channel opening, it potentiates resp onses evoked by the interaction of the natural agonist with presynaptic and postsynaptic nAChR. Allosteric modulation of nAChR activity could therefor e potentially produce a significant benefit in AD. One such allosteric modu lator is galantamine. In addition to increasing nAChR activity, galantamine also inhibits AChE. This novel, dual mechanism of action distinguishes gal antamine from many other AChE inhibitors. Galantamine has been shown to imp rove cognitive and daily function for at least 6 months in placebo-controll ed trials, and to maintain these functions at baseline levels for at least 12 months in a 6-month open-label extension study. Galantamine has positive effects on nAChR expression, which are likely to contribute to its sustain ed efficacy in the treatment of AD patients.