Investigation of anti-cholinesterase and anti-amyloidogenic activities of beta-lactam antibiotics

Objectives: Neuroinflammation is an important factor in the pathogenesis of neurodegenerative disesases. The following study aimed to clarify the effects of beta-lactam antibiotics to the cholinergic system, on acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, considering the structural differences of antibiotics, to evaluate the underlying mechanism of effects provided by protein-antibiotic interactions, and to clarify possible effects of the antibiotics on the aggregation of A beta-peptides. Methods: The inhibition/activation mechanisms for each antibiotic were examined kinetically by Ellman method. Destabilization effects of them on amyloid peptide fibrillation were examined and protein-ligand interactions were evaluated with most potent antibiotics by molecular docking studies. Results: The most powerful inhibitions were detected by the inhibition studies of AChE with ceftazidime (CAZ) and BuChE with amoxicillin (AMX). CAZ was exhibited dose-related dual effect on AChE activity. CAZ was actually the dose-related modifier of AChE. At higher concentrations, CAZ was a nonessential activator of AChE. Molecular docking studies have been confirmed by kinetic studies. Interested beta-lactam antibiotics did not prevent fibrillation rate as rifampicin. Conclusion: Inhibition/activation behaviours of studied beta-lactam antibiotics on both cholinesterases may suggest that cholinergic transmission is one of the crucially important components of the beta-lactam antibiotics-induced central nervous system adverse reactions.