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Harnessing hypoxic adaptation to prevent, treat, and repair stroke.
- Source :
-
Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2007 Dec; Vol. 85 (12), pp. 1331-8. Date of Electronic Publication: 2007 Nov 28. - Publication Year :
- 2007
-
Abstract
- The brain demands oxygen and glucose to fulfill its roles as the master regulator of body functions as diverse as bladder control and creative thinking. Chemical and electrical transmission in the nervous system is rapidly disrupted in stroke as a result of hypoxia and hypoglycemia. Despite being highly evolved in its architecture, the human brain appears to utilize phylogenetically conserved homeostatic strategies to combat hypoxia and ischemia. Specifically, several converging lines of inquiry have demonstrated that the transcription factor hypoxia-inducible factor-1 (HIF1-1) mediates the activation of a large cassette of genes involved in adaptation to hypoxia in surviving neurons after stroke. Accordingly, pharmacological or molecular approaches that engage hypoxic adaptation at the point of one of its sensors (e.g., inhibition of HIF prolyl 4 hydroxylases) leads to profound sparing of brain tissue and enhanced recovery of function. In this review, we discuss the potential mechanisms that could subserve protective and restorative effects of augmenting hypoxic adaptation in the brain. The strategy appears to involve HIF-dependent and HIF-independent pathways and more than 70 genes and proteins activated transcriptionally and post-transcriptionally that can act at cellular, local, and system levels to compensate for oxygen insufficiency. The breadth and depth of this homeostatic program offers a hopeful alternative to the current pessimism towards stroke therapeutics.
- Subjects :
- Adaptation, Physiological
Animals
Brain metabolism
Brain pathology
Brain physiopathology
Enzyme Inhibitors therapeutic use
Humans
Hypoxia, Brain metabolism
Hypoxia, Brain pathology
Hypoxia, Brain physiopathology
Hypoxia-Inducible Factor 1 metabolism
Neuroprotective Agents therapeutic use
Oxidative Stress drug effects
Procollagen-Proline Dioxygenase antagonists & inhibitors
Procollagen-Proline Dioxygenase metabolism
Signal Transduction drug effects
Stroke metabolism
Stroke pathology
Stroke physiopathology
Brain drug effects
Enzyme Inhibitors pharmacology
Hypoxia, Brain drug therapy
Neuroprotective Agents pharmacology
Oxygen metabolism
Stroke drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0946-2716
- Volume :
- 85
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of molecular medicine (Berlin, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 18043901
- Full Text :
- https://doi.org/10.1007/s00109-007-0283-1