Neuroprotective Potential of Synthetic Mono-Carbonyl Curcumin Analogs Assessed by Molecular Docking Studies.

Haya Hussain,Saad Alghamdi,Mehreen Ghias,Mazen Almehmadi,Abid Ullah,Farman Ali Khan,Shafiq Ur Rahman,Juma Muhammad,Osama Abdulaziz,Shujaat Ahmad,Nasir Mehmood Khan,Syed Wadood Ali Shah,Zul Kamal

doi:10.3390/molecules26237168

Abstract

Cognitive decline in dementia is associated with deficiency of the cholinergic system. In this study, five mono-carbonyl curcumin analogs were synthesized, and on the basis of their promising in vitro anticholinesterase activities, they were further investigated for in vivo neuroprotective and memory enhancing effects in scopolamine-induced amnesia using elevated plus maze (EPM) and novel object recognition (NOR) behavioral mice models. The effects of the synthesized compounds on the cholinergic system involvement in the brain hippocampus and their binding mode in the active site of cholinesterases were also determined. Compound h2 (p < 0.001) and h3 (p < 0.001) significantly inhibited the cholinesterases and reversed the effects of scopolamine by significantly reducing TLT (p < 0.001) in EPM, while (p < 0.001) increased the time exploring the novel object. The % discrimination index (DI) was significantly increased (p < 0.001) in the novel object recognition test. The mechanism of cholinesterase inhibition was further validated through molecular docking study using MOE software. The results obtained from the in vitro, in vivo and ex vivo studies showed that the synthesized curcumin analogs exhibited significantly higher memory-enhancing potential, and h3 could be an effective neuroprotective agent. However, more study is suggested to explore its exact mechanism of action.

Highlights

Dementia is related to cognitive decline in brain function, and Alzheimer’s disease (AD) is the most common form of dementia in elderly people, characterized by cognitive decline associated with memory loss, impaired judgment, reasoning and communication; it is a globally growing health challenge [1]
Molecular Docking Study The synthesized compounds were docked using the Molecular Operating Environment (MOE)-Dock protocol to predict their interaction with the targets Acetyl cholinesterase (AChE) and butyryl cholinesterase enzyme (BChE), as well as ligand molecules; the ligX application within the MOE package was used [25]
Molecular Docking Validation of Synthesized Compounds for Anticholinesterases The co-crystallized ligand was re-docked in the acetyl cholinesterase (PDB ID: 2gyu) inhibitor binding cavity after removing the co-crystallized ligand from the active sites

Summary

Introduction

Dementia is related to cognitive decline in brain function, and Alzheimer’s disease (AD) is the most common form of dementia in elderly people, characterized by cognitive decline associated with memory loss, impaired judgment, reasoning and communication; it is a globally growing health challenge [1]. The pathogenesis of dementia is illustrated by the cholinergic hypothesis [4], in which neuronal damage in the septohippocampal cholinergic system progresses the disease [5], leading to loss of memory and cognition [6]. Short-term memory loss is the distinguishing feature of the disease, associated with minor forgetfulness, and after chronic cascade, it leads to death [7]. Alzheimer’s disease remains the focus of enormous amounts of experimental work, yet the exact localization of neuropathological changes essential for memory loss and the underlying cognitive mechanisms remain unexplored [10]

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