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.