BACE1 Inhibitor, Neuroprotective, and Neuritogenic Activities of Melatonin Derivatives

Panyada Panyatip,Emília Sousa,Sarin Tadtong,Ploenthip Puthongking

doi:10.3390/scipharm88040058

Panyada Panyatip, Emília Sousa + Show 2 more

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https://doi.org/10.3390/scipharm88040058

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Abstract

Alzheimer’s disease (AD) is a common chronic neurodegenerative disorders. Melatonin (MLT) has been reported to be neuroprotective agent, and its modified structures exhibit potent antioxidant and anti-inflammation activities. Therefore, the activity of MLT and its derivatives against AD was investigated. Herein, the targeted enzymes, such as β-secretase (BACE1) and acetylcholinesterase (AChE), as well as the neuroprotective and neuritogenic effects on P19-derived neurons were evaluated. All the derivatives (1–5), including MLT, displayed potent inhibitory activity for BACE1, with inhibition values of more than 75% at 5 µM. A molecular docking study predicted that MLT, 5-MT, and 5 bound with BACE1 at catalytic amino acids Asp32 and the flap region, whereas 1–4 interacted with allosteric residue Thr232 and the flap region. The additional π-π interactions between 2, 3, and 5 with Tyr71 promoted ligand-enzyme binding. In addition, MLT, 1, 3, and 5 significantly protected neuron cells from oxidative stress by increasing the cell viability to 97.95, 74.29, 70.80, and 69.50% at 1 nM, respectively. Moreover, these derivatives significantly induced neurite outgrowth by increasing the neurite length and number. The derivatives 1, 3, and 5 should be thoroughly studied as potential AD treatment and neuroprotective agents.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, and the symptoms include loss of memory, difficulty dealing with problems, and disorientation regarding time and place [1]. the etiology of AD is unknown, several pathological hallmarks, such as oxidative stress, amyloid-β (Aβ) deposition, tau protein accumulation, and decreased levels of acetylcholine (ACh), show significant roles in the pathophysiology of this disease [2]
The evaluation of the effects on BACE1 activity revealed that MLT, 5-MT, and all derivatives (1–5)
All the derivatives had inhibitory activities more than 75%, and compound 1 was the most effective in this assay (Table 1)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, and the symptoms include loss of memory, difficulty dealing with problems, and disorientation regarding time and place [1]. the etiology of AD is unknown, several pathological hallmarks, such as oxidative stress, amyloid-β (Aβ) deposition, tau protein accumulation, and decreased levels of acetylcholine (ACh), show significant roles in the pathophysiology of this disease [2]. The cholinergic hypothesis was the first theory proposed to explain AD. A decrease in cholinergic activity is usually observed in the brains of AD patients. Previous studies in both humans and primates have proposed a function of ACh in learning and memory [3,4]. This hypothesis has led to clinical studies uses a type of cholinergic agonist, acetylcholinesterase inhibitors (AChEIs), which exhibited promise in reversing memory loss in AD patients. The US Food and Drug Administration (USFDA) has approved treatments

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