Harnessing hypoxic adaptation to prevent, treat, and repair stroke.
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.
Ratan
Rajiv R
RR
Winifred Masterson Burke Medical Research Institute, White Plains, NY 10605, USA. rratan@burke.org
Siddiq
Ambreena
A
Smirnova
Natalya
N
Karpisheva
Ksenia
K
Haskew-Layton
Renee
R
McConoughey
Stephen
S
Langley
Brett
B
Estevez
Alvaro
A
Huerta
Patricio T
PT
Volpe
Bruce
B
Roy
Sashwati
S
Sen
Chandan K
CK
Gazaryan
Irina
I
Cho
Sunghee
S
Fink
Matthew
M
LaManna
Joseph
J
D000222:Adaptation, Physiological; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D018696:Neuroprotective Agents; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen