Work

Anti-Alzheimer effects of the newly synthesized cationic compounds as multi-target dual hAChE/hBuChE inhibitor: An in silico, in vitro, and in vivo approach

Year: 2024

Type: article

Abstract: Introduction: Multi-target anti-Alzheimer's disease (AD) compounds are promising leads for the development of AD modifying agents. Ionic compounds containing quaternary ammonium moiety were synthesized, and their multi-targeted anti-AD effects were examined. Methods: ) models. The inhibition kinetics of both human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) were assessed. Neuroprotective effects in amyloid-beta (Aβ)-exposed PC12 cells were also examined. Furthermore, the compounds' impact on Aβ-induced memory impairment in Wistar rats was evaluated, with a detailed analysis of the underlying mechanisms. Results: Compound 5g demonstrated acceptable cytotoxicity against human cells. This compound exhibited non-competitive dual inhibition of both hAChE and hBuChE. Additionally, compound 5g mitigated the morphological changes induced by amyloid-beta (Aβ) in PC12 cells and decreased cell mortality. It exhibited anti-oxidative stress properties, evident by reduction in reactive oxygen species (ROS) production, and inhibition of lipid peroxidation. The compound also down regulated the expression of pro-inflammatory genes IL-1β and TNF-α. In vitro studies validated compound 5g's ability to inhibit lactate dehydrogenase (LDH), attenuate neuroinflammation, and prevent the autophagy-apoptosis cascade. When administered to rats with Aβ-induced memory dysfunction, compound 5g enhanced cognitive function and improved spatial memory. In the hippocampi of treated rats, there was a noted downregulation of TNF-α and NF-kB. Furthermore, compound 5g counteracted the elevated activity of AChE. Molecular modeling validated the binding of compound 5g to both steric and catalytic sites of cholinesterase enzymes. Conclusion: studies. Behavioral assessments and molecular analyses further confirmed its therapeutic efficacy in amyloid-beta (Aβ)-challenged rats.

Source: Bioimpacts

DOI: 10.34172/bi.24196