[Acetylcholinesterase inhibitors in Alzheimer's disease: further comments on their mechanisms of action and therapeutic consequences].

Abstract

Cholinergic treatments in Alzheimer's disease are related to the decline of cholinergic central transmission evidenced many years ago in patients. Donepezil, rivastigmine and galantamine have been shown to improve the biodisponibility of acetylcholine at synaptic level by decreasing its enzymatic degradation through acetylcholinesterases. Indeed these cholinesterase inhibitors have shown clinical beneficial effects especially at the early stages of the disease and when the cognitive deterioration is still limited. However, depending on patients, their efficacy can be discussed since the amplitude of the improvement has been recognized as limited. Nevertheless, cholinesterase inhibitors can improve the cognitive capacities or attentional processes in patients and their capability to be autonomous in daily life activities. Differences reported between the three different major cholinesterase inhibitors could be due to different pharmacokinetic and pharmacodynamic properties, especially with regard to the duration and reversibility of acetylcholinesterase inhibition. Since the resulting effect of the different compounds is to increase the synaptic acetylcholine disponibility in all cases, it is generally accepted that therapeutic effects are related to cholinergic stimulation in the brain structures involved in the regulation of cognitive and behavioral processes, with special reference to alpha7 nicotinic receptor subtype, which are concentrated in the cerebral cortex and hippocampal formation. Because of the involvement of such nicotinic receptor subtype in presynaptic activation of numerous neurotransmitters synaptic functions, one can propose that such general stimulation of brain structures contributes to behavioral improvement. Interestingly, data from experimental literature also showed that acetylcholinesterase inhibitors may have neuroprotective effects and could thus act as disease modifiers in patients, slowing the progression of behavioral deterioration since acetylcholinesterases themselves could contribute to the degenerative process. However such a speculative proposal has to be demonstrated in patients.