Modulation of brain acetylcholine levels with cholinesterase inhibitors as a treatment of Alzheimer disease.

The author's hypothesis is that adequate acetylcholine (ACh) hydrolysis inhibition acting through a physiological mechanism could maintain levels of the neurotransmitter sufficient to stimulate postsynaptic receptors which are still active in the brain of patiens affected by senile dementia of Alzheimer type (SDAT). We postulate that the use of reversible and specific cholinesterase inhibitors (ChEI) at optimal concentrations and with a suitable route of adminis tration would be more effective and less toxic than direct cholinergic stimulation by means of cholinomimetic agents. In order to formulate new strategies of treatment with ChEI we should take into consideration distinct differences of these drugs in their effects upon ACh levels in brain. In this review we will describe experimental approaches in animals and experimental treatment in humans which may help us to find optimal levels of ChE inhibition and ACh increases in brain. The effect of repeated doses of ChEI on serum and red blood cell (RBC) ChE activity are also discussed and correlated to the effect of acute and chronic administration on brain ACh. Severity of CNS symptoms seem to correlate more closely to percent of ACh increase in brain than to percent ChE inhibition at peak time or to time of recovery of ChE activity. These experi mental data on animals indicate that "slow release" drugs or intracerebral ad ministration of ChEI may be more effective in raising ACh levels in brain and, therefore, more suitable for therapy of Alzheimer patients.