TY - JOUR
T1 - Defective HIF signaling pathway and brain response to hypoxia in neurodegenerative diseases
T2 - not an "iffy" question!
AU - Correia, Sónia C.
AU - Carvalho, Cristina
AU - Cardoso, Susana
AU - Santos, Renato X.
AU - Plácido, Ana I.
AU - Candeias, Emanuel
AU - Duarte, Ana I.
AU - Moreira, Paula I.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Amyotrophic lateral sclerosis
KW - hypoxia
KW - hypoxia-inducible factor
KW - neurodegeneration
KW - neuroprotection
KW - Parkinson’s disease
UR - http://europepmc.org/abstract/med/23530518
U2 - 10.2174/1381612811319380013
DO - 10.2174/1381612811319380013
M3 - Article
C2 - 23530518
SN - 1381-6128
VL - 19
SP - 6809
EP - 6822
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
IS - 38
ER -