Reappraising neurotransmitter-based strategies

Abstract

A number of observations support the hypothesis that a central deficit in acetylcholine (ACh) may be responsible for the initiation of Alzheimer's disease (AD). For example, cholinergic innervation in AD is reduced in areas of the brain important for processing information. Further, reduced concentrations of choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of ACh, correlate with the number of β-amyloid senile plaques and cognitive dysfunction in AD patients. Consequently, several strategies to increase cholinergic neurotransmission have been developed, including ACh precursors, ACh release enhancers, cholinesterase (ChE) inhibitors and receptor agonists. Although ChE inhibitors appear to be the most promising, tacrine, the first ChE inhibitor to be registered and approved for the treatment of AD, has significant tolerability problems. Thus, ChE inhibitors with improved side-effect profiles have been developed and subsequently awarded marketing approval. However, in addition to the cholinergic system that is the most severely affected neurotransmitter system in AD, other neurotransmitter systems may be involved (e.g. serotonergic, noradrenergic and glutamatergic). Therefore, bifunctional compounds or combinations of drugs may provide additional therapeutic value.