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Mechanisms Behind the Neuroprotective Actions of Cholinesterase Inhibitors in Alzheimer Disease

2006; Lippincott Williams & Wilkins; Volume: 20; Issue: Supplement 1 Linguagem: Inglês

10.1097/01.wad.0000213804.59187.2d

1546-4156

Agneta Nordberg,

Computational Drug Discovery Methods

Inhibitors of the enzyme acetylcholinesterase (AChE) are presently used as long-term symptomatic treatments for patients with Alzheimer disease (AD), as they enhance central levels of synaptic acetylcholine. The accumulation of evidence implicating AChE in the pathogenesis of AD raises the question of whether, in addition to their palliative actions, inhibitors of this enzyme are able to act as disease-modifying agents. In addition to their catalytic effects, there is a suggestion that AChE inhibitors may influence expression of AChE isoforms and increase expression of nicotinic receptors, both of which correlate with cognitive improvements in AD patients. The neuroprotective effect of nicotine, presumably mediated via nicotinic receptors, against β-amyloid (Aβ) toxicity and its effect on amyloid precursor protein (APP) and Aβ production has previously been established. It has also been shown that AChE inhibitors influence APP processing and attenuate Aβ-induced toxicity via mechanisms including interruption of the production of Aβ, alteration of the levels of Aβ 1-50 and 1-52, and formation of the soluble form of APP. Some of these effects seem to occur independently of nicotinic receptors, however. If such experimental in vitro observations can be extrapolated into clinical neuroprotective properties, AChE inhibitors could positively modulate the disease course of AD.