Milameline: Nonselective, Partial Muscarinic Receptor Agonist for the Treatment of Alzheimer's Disease?

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder clinically characterized by a progressive loss of cognitive functions, including memory, language, praxis, judgment and orientation. Many patients also show significant noncognitive symptoms such as depression, psychosis, agitation, and personality changes (40). The etiology of AD remains unknown. Several hypotheses (e.g., amyloid deposition (1), tau hyperphosphorylation (42), metabolic dysfunctions (22), loss of synapses (27), increased oxidative stress (18), immunologic changes (9), and RNA mutations (43)) have been proposed to account for the neurodegenerative process, although the integration of all these different hypotheses into one etiopathogenetical cascade requires further work. One characteristic deficit in AD is the reduction of cholinergic transmission. Basal forebrain neurons, which provide the majority of cholinergic innervation in the cortex and hippocampus, start to degenerate early during the course of AD (45). The cortex and hippocampus show a marked decline in choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of acetylcholine. The number of basal forebrain neurons and the level of ChAT have been shown to correlate with the severity of dementia and the loss of synapses in AD (15). Recent investigations have documented additional cholinergic insufficiencies in other brain regions such as the amygdaloid complex and putamen (11,37). The cholinergic deficit in AD has been a target for pharmacological treatment. Several possible strategies have been explored: – acetylcholine precursors – choline uptake enhancers – acetyl group donors – acetylcholine releasers – acetylcholinesterase inhibitors