Aaptamine - a dual acetyl - and butyrylcholinesterase inhibitor as potential anti-Alzheimer's disease agent.

CONTEXT

Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD.

OBJECTIVE

To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the therapeutic effect on AD in a zebrafish model.

MATERIALS AND METHODS

Aaptamine was isolated from the sponge Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE . Zebrafish were divided into six groups: control, model, 8 μM donepezil, 5 , 10  and 20 μM aaptamine. After three days of drug treatment, the behaviour assay was performed.

RESULTS

The IC values of aaptamine towards AChE and BuChE were 16.0 and 4.6 μM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with values of 6.96 ± 0.04 and 6.35 ± 0.02 μM, with values of 87.6 and 10.7 μM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. studies indicated that the dyskinesia recovery rates of 5 , 10  and 20 μM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%.

DISCUSSION AND CONCLUSIONS

Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.