PRECLINICAL EVIDENCE OF AN ASSOCIATION WITH CHOLINERGIC PRECURSORS AND CHOLINESTERASE INHIBITORS IN AN ANIMAL MODEL OF CEREBRAL VASCULAR DAMAGE

Cholinergic hypofunction is a trait of Alzheimer’s disease (AD)and of other forms of dementias such as vascular dementia (VaD) and Lewy bodies dementia (LBD). The acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) are one of the two classes of drug approved for AD treatment. ChE-Is are licensed for the symptomatic relief of mild to moderate AD. These drugs are used out of label as a therapeutic approach for treating cognitive disorders other than AD such as VaD and LBD. A main problem deriving from their use is that the benefits of AD symptomatic treatment are modest and not long lasting. It is also thought that the magnitude of benefit of this class of drugs can elicit is apparently marginal and difficult to detect and to measure clinically. Moreover, widespread use of AChE/ChE inhibitors may be accompanied by serious adverse events. Cholinergic precursors represent an old approach to treat cholinergic dysfunction, but the first drugs proposed did not show clinical benefit on symptoms of AD. Actually, evidence for an enhancement of ACh biosynthesis by choline or lecithin is faint. The same is not true for cytidine 5'- diphosphocholine and choline alphoscerate for which a modest improvement of cognitive dysfunction in dementia disorders is documented. The association of ChE-Is with phospholipids involved in choline biosynthetic pathways was proposed to further enhance cholinergic neurotransmission compared to single compounds. It could represent a strategy to provide a stronger cholinergic challenge in dementia. This study reviews the cholinergic hypothesis of geriatric memory dysfunction and discusses based on original finding the neurochemical bases of the association between ChE-Is and cholinergic precursors. Evidence of a possible neuroprotective effect of the association in animal models is also presented