Salidroside mediated stabilization of Bcl -xL prevents mitophagy in CA3 hippocampal neurons during hypoxia.

Abstract

Chronic hypoxic stress results in deposition of lipofuscin granules in the CA3 region of hippocampal neurons which contributes to neurodegeneration and accelerated neuronal aging. Oxidative stress and mitophagy during hypoxia are crucial to cause aggregation of these lipofuscin granules in hypoxic neurons. Salidroside, a glucoside derivative of β-Tyrosol, has been reported to protect hypoxic neurons through maintenance of mitochondrial activity. The present study is aimed at investigating the potential of Salidroside in preventing mitophagy during chronic hypoxia and identification of the molecular targets and underlying signaling mechanisms. In-silico analysis for interaction of salidroside with Bcl-xL was carried out using VLife MDS software. The prophylactic efficacy of Salidroside for amelioration of global hypoxia induced neuronal aging was studied in adult male Sprague-Dawley rats exposed to hypobaric hypoxia simulating an altitude of 7600 m for 21 days. Salidroside was supplemented at a daily dose of 25 mg kg-1b.w. p.o. during hypoxic exposure. Ultra-structural and immune-histological studies were conducted to study lipofuscin aggregation and mitophagy. In-silico findings on salidroside mediated stabilization of Bcl-xL were validated by investigating its effect on downstream signaling molecules involved in mitophagy. Administration of Salidroside reduced deposition of lipofuscin in hypoxic CA3 hippocampal neurons and prevented mitophagy. Salidroside stabilizes Bcl-xL in hypoxic neurons resulting in inhibition of PGAM5 phosphatase activity and maintenance of FUNDC1 in phosphorylated state. Salidroside mediated inhibition of pFUNDC1 dephosphorylation prevents FUNDC1-LC3 II interaction which is crucial for mitophagy. The present study demonstrates potential of Salidroside in preventing lipofuscin deposition during chronic hypoxic stress.

• Authors: Suryanarayan Biswal, Kalpana Kumari Barhwal, Debashree Das, Richa Dhingra, Nilima Dhingra, Tapas Chanda Nag, Sunil Kumar Hota
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 116 Pg. 39-52 (08 2018) ISSN: 1095-953X [Electronic] United States
• PMID: 29723606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• Bcl2l1 protein, rat
• Glucosides
• Phenols
• bcl-X Protein
• rhodioloside

Topics

• Animals
• Autophagy (drug effects, physiology)
• CA3 Region, Hippocampal (drug effects, metabolism, ultrastructure)
• Glucosides (metabolism, pharmacology)
• Hypoxia, Brain (metabolism, pathology)
• Male
• Mitophagy (drug effects, physiology)
• Molecular Docking Simulation (methods)
• Neurons (drug effects, metabolism, ultrastructure)
• Phenols (metabolism, pharmacology)
• Protein Structure, Secondary
• Rats
• Rats, Sprague-Dawley
• bcl-X Protein (chemistry, metabolism)