Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer's Disease Therapy

Abstract

Alzheimer's disease (AD) is a main cause of dementia, accounting for up to 75% of all dementia cases. Pathophysiological processes described for AD progression involve neurons and synapses degeneration, mainly characterized by cholinergic impairment. This feature makes acetylcholinesterase inhibitors (AChEi) the main class of drugs currently used for the treatment of AD dementia phase, among which galantamine is the only naturally occurring substance. However, several plant species producing diverse classes of alkaloids, coumarins, terpenes, and polyphenols have been assessed for their anti-AChE activity, becoming potential candidates for new anti-AD drugs. Therefore, this mini-review aimed to recapitulate last decade studies on the anti-AChE activity of plant species, their respective extracts, as well as isolated compounds. The anti-AChE activity of extracts prepared from 54 plant species pertaining 29 families, as well as 36 isolated compounds were classified and discussed according to their anti-AChE pharmacological potency to highlight the most prominent ones. Besides, relevant limitations, such as proper antioxidant assessment, and scarcity of toxicological and clinical studies were also discussed in order to help researchers out with the bioprospection of potentially new AChEi.

Keywords: Alzheimer's disease; acetylcholinesterase inhibitors; anti-cholinesterase; plant species; secondary metabolites.

Figure 1

Schematic view of acetylcholinesterase active binding sites for the main natural acetylcholinesterase inhibitors (AChEi) classes. (A) Acetylcholinesterase gorge pocket composed by the following binding sites: esteratic site, anionic site, peripheral anionic site (PAS), as well as hydrophobic pocket (HP) is shown. Colored circles represent the main binding sites for compounds pertaining to the indicated classes. (B) Natural AChEi reported in Pubmed from 2007 to 2018 (1st semester) were classified in accordance with the criteria described at Section Natural AChEi Compounds in: high potency (green background), moderate potency (orange background), and low potency (red background). The diamond symbol represents the IC₅₀ value for each compound (in the left) as described in the respective study (in the right).