BRAIN SELECTIVE-INHIBITION OF ACETYLCHOLINESTERASE - A NOVEL-APPROACH TO THERAPY FOR ALZHEIMERS-DISEASE

Publisher Summary Alzheimer's disease (AD) is a degenerative disorder of the CNS, which will become a major health problem in the following decades. The search for causes and possible treatments for AD becomes more and more urgent as the world population ages, and therefore, the disease represents a major public problem because of the severity of the accompanying disabilities increasing the economically costly conditions. To date, no effective therapy exists and diagnosis is still a problem, often confirmed only postmortem. The pathogenesis and the aetiology remain unknown although many factors involved in this disease have been suggested and studied, including genetic disposition, abnormal protein processing, toxins, infectious agents, and neurotransmitter deficits. The strong commitment of the cholinergic system in AD may account for the observed cognitive deficit, but it is unlikely to explain the whole range of deficits observed within the disease. The existence of an underactive central cholinergic system measured postmortem in brains of AD patients has led to the so called “cholinergic deficit hypothesis” and further to clinical trials of cholinergic drugs to attempt to reverse the deficit. From the three major categories of cholinergic approaches— namely, (i) precursor administration; (ii) administration of direct acting agonists; (iii) inhibition of acetylcholinesterase (AChE); (iv) the approach of AChE inhibition seems to show symptomatic improvements at least in some clinical trials. In general, AChE inhibitors of the carbamate type show such a long-lasting inhibition due to their mechanism of action, in the past, they were also called “pseudo-irreversible” inhibitors. The advantageous pharmacological profile of such a brain selective AChE-I is described in this chapter, as well as its influence in vitro on AChE derived from the AD brains.