Post-treatment with apocynin at a lower dose regulates the UPR branch of eIF2α and XBP-1 pathways after stroke.

Autor: Nakka VP; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, 500046, India; Department of Biochemistry, Acharya Nagarjuna University, Andhra Pradesh 522510, India., Gogada R; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, 500046, India; Department of Biochemistry and Plant Physiology, M.S. Swaminathan School of Agriculture, Centurion University of Technology and Management, Odisha 761211, India., Simhadri PK; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, 500046, India., Qadeer MA; Biological E. Limited, Hyderabad 500078, India., Phanithi PB; Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, 500046, India. Electronic address: prakash@uohyd.ac.in.
Jazyk: angličtina
Zdroj: Brain research bulletin [Brain Res Bull] 2022 May; Vol. 182, pp. 1-11. Date of Electronic Publication: 2022 Feb 07.
DOI: 10.1016/j.brainresbull.2022.02.003
Abstrakt: Stroke leads to disturbance in the physiology of the ER (Endoplasmic Reticulum) that triggers UPR (Unfolded Protein Response) pathways aimed to compensate neuronal cell damage. However, sustained UPR causes stressful conditions in the ER lumen forming abnormal protein aggregates. Stroke-induced oxidative stress also amalgamates with UPR to safeguard and ensure the proper functioning of brain cells. Thus we tested the effect of apocynin (a potent antioxidant) post-treatment in experimental stroke on the outcome of ER stress and UPR branch pathways. We administered a low dose of apocynin at 1 mg/kg (intraperitoneal) to adult Sprague-Dawley rats subjected to Middle Cerebral Artery Occlusion (MCAO) for two-time points. The first dose immediately after re-establishing the blood flow and another at 6 h of reperfusion. Apocynin post-treatment significantly reduced ROS (Reactive Oxygen Species) generation at an early reperfusion time point of 4 h. It preserved neuronal morphology, dendritic spine density, reduced protein aggregation, and brain damage after 24 h of reperfusion. Apocynin post-treatment regulates the two UPR branch pathways in our experimental paradigm. 1) Down-regulation of eIF2α (Eukaryotic Initiation Factor 2α) phosphorylation, and CHOP (C/EBP homologous protein) 2) by reducing the XBP-1 (X-Box binding Protein-1) mRNA splicing downstream to PERK (Protein Kinase RNA-Like ER Kinase) and IRE1α (Inositol Requiring Enzyme 1alpha) UPR pathways, respectively. Bioinformatics prediction showed that apocynin has binding sites for PERK (Protein Kinase RNA-Like ER Kinase) and IRE1α proteins. The amino acid residues interacting with apocynin were Cys891 and Gln889 (for PERK), and the amino acids Ser726, Arg722, and Ala719 (for IRE1α) lying within their activation loop. Overall, these studies indicate that apocynin post-treatment might regulate ER stress/UPR pathways and minimize stroke brain damage, thus having implications for developing newer strategies for stroke treatment.
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
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