THE ROLE OF CHOLINESTERASE-INHIBITORS IN ALZHEIMERS-DISEASE

Alzheimer's disease is the most prevalent late-onset neurodegenerative disorder of unknown origin. The cholinergic hypothesis of Alzheimer's disease attributes the cognitive deficits of the disease and their severity to the degeneration of cholinergic pathways running from the nucleus basalis of Meynert to the hippocampus. Five basic strategies have been pursued to treat the disorder: precursor loading, increasing the release of acetylcholine, decreasing the degradation of acetylcholine, activating cholinergic receptors and stimulating intracellular second messengers. Based on the strategy of reducing the degradation of acetylcholine, cholinesterase inhibitors were developed. By inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine, these agents make more acetylcholine available to postsynaptic neurons. It was suggested that cholinesterase inhibitors could reverse memory impairment, and they are now being investigated and/or used to restore acetylcholine deficits at synaptic sites in the brain. A number of cholinesterase inhibitors have been shown to be moderately effective in mild to moderate Alzheimer's disease. Among their adverse effects, reversible increases in liver transaminase levels cause the most concern. The drugs also will, in a dose-dependent manner, cause typical cholinergic adverse effects, affecting mainly the gastrointestinal system.