Neuroprotective Effects of Activated Protein C Involve the PARP/AIF Pathway against Oxygen-Glucose Deprivation in SH-SY5Y Cells.

Mukesh Kumar Sriwastva,Renu Saxena,Mutahar Andrabi,Kameshwar Prasad,Remesh Kunjunni,Vivekanandhan Subbiah

doi:10.3390/brainsci10120959

Mukesh Kumar Sriwastva, Renu Saxena + Show 4 more

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https://doi.org/10.3390/brainsci10120959

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Journal: Brain sciences	Publication Date: Dec 10, 2020
Citations: 3	License type: CC BY 4.0

Affiliation: All India Institute of Medical Sciences

Abstract

Protein C, a member of the zymogen family of serine proteases in plasma, is one of the several vitamin K dependent glycoproteins known to induce anti-apoptotic activity. However, the target molecule involved in the mechanism needs to be investigated. We sought to investigate the pathways involved in the anti-apoptotic role of activated protein C (APC) on oxygen-glucose deprivation (OGD) induced ischemic conditions in in-vitro SH-SY5Y cells. SH-SY5Y cells were exposed to OGD in an airtight chamber containing 95% N2 and 5% CO2 and media deprived of glucose for 4 h following 24 h of reoxygenation. The cell toxicity, viability, expression of receptors such as endothelial cell protein C receptor (EPCR), protease-activated receptor (PAR)1, PAR3, and apoptosis-related proteins B-cell lymphoma 2 (BCL-2), BCL-2-like protein 4 (Bax), Poly [ADP-ribose] polymerase-1 (PARP-1) were assessed. Administration of APC decreased the cellular injury when compared to the OGD exposed group in a dose-dependent manner and displayed increased expression of PAR-1, PAR-3, and EPCR. The APC treatment leads to a reduction in PARP-1 expression and cleavage and apoptosis-inducing factor (AIF) expression. The reduction of caspase-3 activity and PARP-1 and AIF expression following APC administration results in restoring mitochondrial function with decreased cellular injury and apoptosis. Our results suggested that APC has potent protective effects against in-vitro ischemia in SH-SY5Y cells by modulating mitochondrial function.

Highlights

Ischemic stroke is the second leading cause of death and the leading cause of long-term adult disability worldwide [1]
Increase in cell death was in Figure consecutive gradual decrease in cell viability percentage was continued in all observed at 2 h oxygen-glucose deprivation (OGD) exposure compared to the control group, as depictedfurther in
apoptosis-inducing factor (AIF) expression, both of which are reported as contributing to ischemic injury, which leads to apoptosis

Summary

Introduction

Ischemic stroke is the second leading cause of death and the leading cause of long-term adult disability worldwide [1]. A number of clinical trials have been carried out to investigate the potential neuroprotective compounds of ischemic strokes [2]. The researchers have targeted the development of multi-target strategies to protect neuronal cells following ischemic injury. Protein C, a member of the zymogen family of serine proteases in plasma, is one of several vitamin K dependent glycoproteins. Cleavage of protein C at Arg169 by thrombin removes the activation peptide and generates activated protein C (APC) [3]. The anticoagulant characteristics of APC have been well-studied [4,5].

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