Donepezil dose-dependently inhibits acetylcholinesterase activity in various areas and in the presynaptic cholinergic and the postsynaptic cholinoceptive enzyme-positive structures in the human and rat brain

In the symptomatic treatment of mild to moderately severe dementia associat ed with Alzheimer's disease, donepezil (E2020) has been introduced for the inhibition of acetylcholinesterase activity in the human brain. However, th ere is no morphological evidence as to how this chemical agent affects the acetylcholinesterase positive structures in the various areas of the human and the rat CNS. This study demonstrates by histochemical means that donepe zil exerts a dose-dependent inhibitory effect in vitro on acetylcholinester ase activity. The most sensitive areas were the cortex and the hippocampal formation. Within the different layers of the cortex, the cholinoceptive ac etylcholinesterase-positive postsynaptic pyramidal cell bodies were more se nsitive than the presynaptic cholinergic axonal processes. In the cortex, t he cell body staining was already abolished by even 2 x 10(-8) M donepezil, whereas the axonal staining could be eliminated only by at least 5 x 10(-8 ) M donepezil. Ln the hippocampus, the axonal acetylcholinesterase reaction end-product was eliminated by 5 x 10(-7) M donepezil. The most resistant r egion was the putamen, where the staining intensity was moderately reduced by 1 x 10(-6) M donepezil. In the rat brain, the postsynaptic cholinoceptiv e and presynaptic cholinergic structures were inhibited by nearly the same dose of donepezil as in the human brain. These histochemical results provid e the first morphological evidence that, under in vitro circumstances, done pezil is not a general acetylcholinesterase inhibitor in the CNS. but rathe r selectively affects the different brain areas and, within these, the chol inoceptive and cholinergic structures. The acetylcholinesterase staining in the nerve fibers (innervating the intracerebral blood vessels of the human brain and the extracerebral blood vessels of the rat brain) and at the neu romuscular junction in the diaphragm and gastrocnemius muscle of rat, was a lso inhibited dose dependently by donepezil. It is concluded that donepezil may be a valuable tool with which to influen ce both the pre- and the postsynaptic acetylcholinesterase-positive structu res in the human and rat central and peripheral nervous systems. (C) 2000 I BRO. Published by Elsevier Science Ltd. All rights reserved.