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Brain‐derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF‐mediated pro‐death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague–Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro‐BDNF and alteration in N‐linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose‐regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase β (Trkβ) in non‐raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkβ from non‐raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkβ from non‐raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation‐induced alteration in raft dynamics which is promotes p75 receptor‐mediated death signalling in hippocampal neurons during chronic hypoxia. BDNF mediated neurodegeneration in hypoxia through p75 neurotrophin receptor. however, underlying mechanisms are unknown. The present study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Our finding revealed Hypoxia induced endoplasmic reticulum stress alters glycosylation of pre‐proBDNF leading to increased expression of pro‐BDNF. Hypoxia also results in increased localization of p75/p75 dimers in the raft fraction resulting in death receptor mediated apoptosis of hippocampal CA1 neurons. Future studies in this direction may provide a breakthrough in developing suitable prophylactic and therapeutic strategies for ameliorating hypoxic neurodegeneration. [ABSTRACT FROM AUTHOR]

Neuronal damage in hypoxia and several neurodegenerative disorders is invariably associated with oxidative damage and mitochondrial dysfunction. Administration of acetyl- L-carnitine (ALCAR) on the other hand attenuates neuronal damage, prevents apoptosis, and improves energy status in hypoxic stress through less understood mechanisms. Becasue mitochondrial biogenesis could be a possible mechanism for ALCAR-induced improvement in bioenergetics in neurons, the present study aimed at exploring signaling pathways of ALCAR-induced neuroprotection in hypoxia and possible occurrence of mitochondrial biogenesis. To create global hypoxia, adult Sprague-Dawley rats were exposed to a simulated altitude of 7,620 m at standard temperature and humidity conditions. We here demonstrate that administration of ALCAR to hypoxic rats for a period of 2 weeks effectively protected hippocampal neurons from mitochondrial dysfunction, excitotoxicity, and neurodegeneration. ALCAR administration resulted in peroxisome proliferator-activated receptor γ coactivator-1α and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism. Most notably, calcium buffering into nonfunctional mitochondria ameliorated excitotoxicity and improved bioenergetic status of the hippocampal neurons. Together, the data reveal the immense therapeutic potential of ALCAR for the treatment of ischemia, stroke, and other neurodegenerative disorders associated with hypoxic stress and excitotoxicity. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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-x L 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 -1 b.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-x L 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-x L 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., (Copyright © 2018. Published by Elsevier Inc.)