Abstract
Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the “headquarter” of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus, enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response to hypoxia and its close association with the development of Alzheimer’s, and Parkinson’s disease and amyotrophic lateral sclerosis. Finally, the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.
Keywords: Alzheimer’s disease, Amyotrophic lateral sclerosis, hypoxia, hypoxia-inducible factor, neurodegeneration, neuroprotection, Parkinson’s disease
Current Pharmaceutical Design
Title:Defective HIF Signaling Pathway and Brain Response to Hypoxia in Neurodegenerative Diseases: Not an “Iffy” Question!
Volume: 19 Issue: 38
Author(s): Sónia C. Correia, Cristina Carvalho, Susana Cardoso, Renato X. Santos, Ana I. Plácido, Emanuel Candeias, Ana I. Duarte and Paula I. Moreira
Affiliation:
Keywords: Alzheimer’s disease, Amyotrophic lateral sclerosis, hypoxia, hypoxia-inducible factor, neurodegeneration, neuroprotection, Parkinson’s disease
Abstract: Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the “headquarter” of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus, enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response to hypoxia and its close association with the development of Alzheimer’s, and Parkinson’s disease and amyotrophic lateral sclerosis. Finally, the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.
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Cite this article as:
C. Correia Sónia, Carvalho Cristina, Cardoso Susana, X. Santos Renato, I. Plácido Ana, Candeias Emanuel, I. Duarte Ana and I. Moreira Paula, Defective HIF Signaling Pathway and Brain Response to Hypoxia in Neurodegenerative Diseases: Not an “Iffy” Question!, Current Pharmaceutical Design 2013; 19 (38) . https://dx.doi.org/10.2174/1381612811319380013
DOI https://dx.doi.org/10.2174/1381612811319380013 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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