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Review
. 2019 Jan 8:6:175.
doi: 10.3389/fcell.2018.00175. eCollection 2018.

Hypoxia Mimetic Agents for Ischemic Stroke

Charles K Davis  1 , Saurabh A Jain  2 , Ok-Nam Bae  3 , Arshad Majid  2 , G K Rajanikant  1
Affiliations
Review

Hypoxia Mimetic Agents for Ischemic Stroke

Charles K Davis et al. Front Cell Dev Biol. .

Abstract

Every year stroke claims more than 6 million lives worldwide. The majority of them are ischemic stroke. Small molecule-based therapeutics for ischemic stroke has attracted a lot of attention, but none has been shown to be clinically useful so far. Hypoxia-inducible factor-1 (HIF-1) plays a crucial role in the transcriptional adaptation of cells to hypoxia. Small molecule-based hypoxia-mimetic agents either stabilize HIF-1α via HIF-prolyl hydroxylases (PHDs) inhibition or through other mechanisms. In both the cases, these agents have been shown to confer ischemic neuroprotection in vitro and in vivo. The agents which act via PHD inhibition are mainly classified into iron chelators, iron competitors, and 2 oxoglutarate (2OG) analogs. This review discusses HIF structure and key players in the HIF-1 degradation pathway as well as the genes, proteins and chemical molecules that are connected to HIF-1 and how they affect cell survival following ischemic injury. Furthermore, this review gives a summary of studies that used PHD inhibitors and other HIF-1α stabilizers as hypoxia-mimetic agents for the treatment of ischemic injury.

Keywords: hypoxia mimetic agent; hypoxia-inducible factor-1; iron chelators; ischemic stroke; neuroprotection.

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Figures

FIGURE 1
FIGURE 1
Network showing HIF-1 connected to its target genes (adapted from: http://www.grnpedia.org/trrust/). Colors inside the shape represent the type of interaction.
FIGURE 2
FIGURE 2
Domain structure of human HIF subunits and isoforms.
FIGURE 3
FIGURE 3
Regulation of HIF-1 during hypoxia and normoxia.
See this image and copyright information in PMC

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