Antioxidant Activity and Neuroprotective Activity of Stilbenoids in Rat Primary Cortex Neurons via the PI3K/Akt Signalling Pathway.

Haichao Wen,Zheng Fu,Liyan Ma,Xiaoxu Zhang,Yangji Wei,Liwei Gu,Jingming Li

doi:10.3390/molecules23092328

Abstract

Antioxidant activity and neuroprotective activity of three stilbenoids, namely, trans-4-hydroxystilbene (THS), trans-3,5,4′-trihydroxy-stilbene (resveratrol, RES), and trans-3′,4′,3,5-tetrahydroxy-stilbene (piceatannol, PIC), against β-amyloid (Aβ)-induced neurotoxicity in rat primary cortex neurons were evaluated. THS, RES, and PIC significantly scavenged DPPH• and •OH radicals. All three stilbenoids were able to inhibit Aβ neurotoxicity by decreasing intracellular reactive oxygen species (ROS) via the PI3K/Akt signalling pathway. Specifically, stilbenoids significantly promoted Akt phosphorylation; suppressed Bcl-2/Bax expression; and inhibited caspase-9, caspase-3, and PARP cleavage. Molecular docking between stilbenoids with Akt indicated that stilbenoids could form hydrogen bond interactions with the COOH-terminal region of Akt. Additionally, the neuroprotective activity of stilbenoids correlated with the number and position of hydroxyl groups. The lack of meta-dihydroxyl groups on THS did not affect its neuroprotective activity in comparison with RES, whereas the ortho-dihydroxyl moiety on PIC significantly enhanced neuroprotective activity. These results provide new insights into the correlation between the biological activity and chemical structure of stilbenoids.

Highlights

Alzheimer’s disease, the most common form of dementia worldwide, is a neurodegenerative disorder characterized by the loss of neurons in the brain and cognitive decline
DPPH and OH were examined by electron paramagnetic resonance (EPR) spectroscopy to detect the presence of unpaired electrons
The scavenging activity of DPPH and OH followed the sequence PIC > RES > THS, which indicates that the antioxidant capacity of stilbenoid increased with the number of hydroxyl substituents to a certain extent

Summary

Introduction

Alzheimer’s disease, the most common form of dementia worldwide, is a neurodegenerative disorder characterized by the loss of neurons in the brain and cognitive decline. In the Molecules 2018, 23, 2328; doi:10.3390/molecules23092328 www.mdpi.com/journal/molecules “amyloid cascade hypothesis” of Alzheimer’s disease pathogenesis, neurotoxic Aβ accumulation in the brain has been considered an important cause of Alzheimer’s disease development [2,3]. Aβ peptides are formed by proteolytic cleavage of the amyloid precursor protein (APP) by β-secretase and γ-secretase [4]. The ROS overproduction caused by oxidative stress and Aβ result in direct oxidative damage to cellular DNA, lipids, and proteins, followed by cellular structural damage, cellular function disorder, and cell apoptosis [5]. Aβ and ROS accumulation induces neurotoxicity by interacting with protein kinase and lipid kinase signalling cascades [8,9]

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