Selective inhibitors of butyrylcholinesterase: a valid alternative for therapy of Alzheimer's disease?

Abstract

The brain of mammals contains two major forms of cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and in their kinetics. Butyrylcholine is not a physiological substrate in mammalian brains which makes the function of BuChE difficult to interpret. In human brains, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in patients with Alzheimer's disease (AD). While AChE activity decreases progressively in the brain of patients with AD, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor. We found that extracellular acetylcholine levels increased 15-fold from 5 nmol/L to 75 nmol/L concentrations, with little cholinergic adverse effect in the animal. Based on these data, we postulated that two pools of ChEs may be present in the brain: one mainly neuronal and AChE dependent; and one mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of acetylcholine concentration in the brain and can be separated with selective inhibitors. The recent development of highly selective BuChE inhibitors will allow us to test these new agents in patients with AD in order to find out whether or not they represent an advantage for the treatment of patients with AD as compared with selective (donepezil) or relatively non-selective (rivastigmine, galantamine) ChE inhibitors presently in use. The association between a BuChE-K variant and AD has not been confirmed in several studies. In conclusion, additional experimental and clinical work is necessary in order to elucidate the role of BuChE in normal brain function and in the brains of patients with AD. In the future, it may be possible that selective BuChE inhibitors will have a role in treatment of patients with advanced AD.