IS THERE A RATIONALE FOR THE USE OF ACETYLCHOLINESTERASE INHIBITORS IN THE THERAPY OF ALZHEIMERS-DISEASE

Since the 1980s, the cholinergic hypothesis of the pathogenesis of Alz heimer's disease has proven to be a strong stimulus to pharmacological strategies aimed at correcting the cognitive deficit by manipulating cholinergic neurotransmission. Among these strategies, the one based o n acetylcholinesterase inhibition is currently the most extensively de veloped for the therapy of Alzheimer's disease. The inhibitors' mechan isms of action are complex, including changes in the release of acetyl choline, and modulation of acetylcholine receptors. Various clinical t rials of various inhibitors have shown that, on the whole, their effec ts were modest and, in the case of some drugs, were associated with fr equent adverse reactions. Among the conceivable reasons for the limite d efficacy of these drugs, those related to the pharmacological target deserve particular attention. This review, therefore, focuses on the complex nature of the acetylcholine system, the alterations of acetylc holinesterase and muscarinic receptor signal transduction in Alzheimer 's disease, and the involvement of other neurotransmitters. (C) 1998 E lsevier Science B.V.