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Phytomedicine

Phytomedicine

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THSG alleviates cerebral ischemia/reperfusion injury via the GluN2B–CaMKII–ERK1/2 pathway

Published:6 April 2024 DOI:
Tonghe Liu , Jiayi Shi , Dahua Wu , Dandan Li , Yuhong Wang , Jian Liu , Pan Meng , Lijuan Hu , Chaojun Fu , Zhigang Mei , Jinwen Ge , Xiuli Zhang

Abstract

Background

The potential therapeutic targeting of PINK1-PARK2-mediated mitophagy against cerebral ischemia/reperfusion (CI/R) injury involves the pathophysiological processes of neurovascular unit (NVU) and is closely associated with N-methyl-D-aspartate receptors (NMDARs) commonly expressed in NVU. 2,3,5,4′-Tetrahydroxy-stilbene-2-O-β-D-glucoside (THSG), a compound derived from the traditional Chinese medicine Polygonum multiflorum Thunb., has demonstrated notable neuroprotective properties against CI/R injury. However, it remains unclear whether THSG exerts its protective effects through GluN2B related PINK1/ PARK2 pathway.

Purpose

This study aims to explore the pharmacological effects of THSG on alleviating CI/R injury via the GluN2B–CaMKII–ERK1/2 pathway.

Methods

THSG neuroprotection against CI/R injury was studied in transient middle cerebral artery occlusion/reversion (tMCAO/R) model rats and in oxygen and glucose deprivation/ reoxygenation (OGD/R) induced neurons. PINK1–PARK2-mediated mitophagy involvement in the protective effect of THSG was investigated in tMCAO/R rats and OGD/R-induced neurons via THSG and 3-methyladenine (3-MA) treatment. Furthermore, the beneficial role of GluN2B in reperfusion and its contribution to the THSG effect via CaMKII–ERK1/2 and PINK1–PARK2-mediated mitophagy was explored using the GluN2B-selective antagonist Ro 25–6981 both in vivo and in vitro. Finally, the interaction between THSG and GluN2B was evaluated using molecular docking.

Results

THSG significantly reduced infarct volume, neurological deficits, penumbral neuron structure, and functional damage, upregulated the inhibitory apoptotic marker Bcl-2, and suppressed the increase of pro-apoptotic proteins including cleaved caspase-3 and Bax in tMCAO/R rats. THSG (1 μM) markedly improved the neuronal survival under OGD/R conditions. Furthermore, THSG promoted PINK1 and PARK2 expression and increased mitophagosome numbers and LC3-II–LC3-I ratio both in vivo and in vitro. The effects of THSG were considerably abrogated by the mitophagy inhibitor 3-MA in OGD/R-induced neurons. Inhibiting GluN2B profoundly decreased mitophagosome numbers and OGD/R-induced neuronal viability. Specifically, inhibiting GluN2B abolished the protection of THSG against CI/R injury and reversed the upregulation of PINK1–PARK2-mediated mitophagy by THSG. Inhibiting GluN2B eliminated THSG upregulation of ERK1/2 and CaMKII phosphorylation. The molecular docking analysis results demonstrated that THSG bound to GluN2B (binding energy: –5.2 ± 0.11 kcal/mol).

Conclusions

This study validates the premise that THSG alleviates CI/R injury by promoting GluN2B expression, activating CaMKII and ERK1/2, and subsequently enhancing PINK1–PARK2-mediated mitophagy. This work enlightens the potential of THSG as a promising candidate for novel therapeutic strategies for treating ischemic stroke.

Substances (21)

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3-METHYLADENINE 5142-23-4 C6H7N5 397 suppliers $12.00-$4500.00
3-METHYLADENINE 5142-23-4 C6H7N5 397 suppliers $12.00-$4500.00
3-METHYLADENINE 5142-23-4 C6H7N5 397 suppliers $12.00-$4500.00
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NVP-AAM077 459836-30-7 C17H17BrN3O5P 89 suppliers $44.00-$4173.50
NVP-AAM077 459836-30-7 C17H17BrN3O5P 89 suppliers $44.00-$4173.50
NVP-AAM077 459836-30-7 C17H17BrN3O5P 89 suppliers $44.00-$4173.50
NVP-AAM077 459836-30-7 C17H17BrN3O5P 89 suppliers $44.00-$4173.50
tetrahydroxyl diphenylethylene-2-o-glucoside 55327-45-2 C20H22O9 81 suppliers Inquiry
tetrahydroxyl diphenylethylene-2-o-glucoside 55327-45-2 C20H22O9 81 suppliers Inquiry
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