Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

Background and purpose: The acetylcholinesterase inhibitor, donepezil, is also a high affinity s 1 receptor agonist. We examined the involvement of s 1 receptors in its anti-amnesic and neuroprotective properties against amyloid b 25-35 peptideinduced toxicity in mice. Experimental approach: Mice were given an intracerebroventricular (i.c.v.) injection of Ab 25-35 peptide (9 nmol) 7-9 days before being tested for spontaneous alternation and passive avoidance. Hippocampal lipid peroxidation was measured 7 days after Ab 25-35 injection to evaluate oxidative stress. Donepezil, the s 1 agonist PRE-084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti-amnesic effects, or 20 min before Ab 25-35 injection, or 24 h after Ab 25-35 injection and then once daily before behavioural sessions, to check their pre-and post-i.c.v. neuroprotective activity, respectively. Key results: All the drugs tested were anti-amnesic, but only the effects of PRE-084 and donepezil were prevented by the s 1 antagonist BD1047. Only PRE-084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE-084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE-084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors. Conclusions and implications. The potent anti-amnesic and neuroprotective effects of donepezil against Ab 25-35 -induced toxicity involve both its cholinergic and s 1 agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors.

Use of donepezil by AD patients resulted in significant delays in NHP. Long-term use of donepezil may help AD patients live longer in community settings, with consequent personal, social, and economic benefits.

These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.

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