Hypoxia-inducible factor prolyl hydroxylases as targets for neuroprotection by “antioxidant” metal chelators: From ferroptosis to stroke

Abstract

Neurologic conditions including stroke, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are leading causes of death and long-term disability in the United States, and efforts to develop novel therapeutics for these conditions have historically had poor success in translating from bench to bedside. Hypoxia Inducible Factor-1alpha (HIF-1α) mediates a broad, evolutionarily conserved, endogenous adaptive program to hypoxia, and manipulation of components of the HIF pathway are neuroprotective in a number of human neurological diseases and experimental models. In this review, we discuss molecular components of one aspect of hypoxic adpatation in detail, and provide perspective on which targets within this pathway appear to be ripest for preventing and repairing neurodegeneration. Further, we highlight the role of HIF prolyl hydroxylases as emerging targets for the salutary effects of metal chelators on ferroptosis in vitro as well in animal models of neurological diseases.

BID links ferroptosis to mitochondrial cell death pathways

“…In addition to iron-chelating compounds, ferroptosis can be blocked by ferrostatin-1, a potent inhibitor which mediates protective effects against erastin-induced ferroptosis by inhibiting lipid peroxidation [27], [7]. Further, mechanisms of ferroptosis have been identified in neurons, in death signaling pathways induced by cerebral ischemia [22] and in glutamate-induced neurotoxicity in organotypic hippocampal slice cultures [7]. Similarly as in glutamate-induced oxytosis, erastin activates ferroptosis by inhibiting the X c - transporter.…”

Genome maintenance and bioenergetics of the long-lived hypoxia-tolerant and cancer-resistant blind mole rat, Spalax: a cross-species analysis of brain transcriptome

“…The mammalian brain is a highly oxygen-dependent organ that consumes high percentage of the body oxygen relative to its size (in humans, about 20% of the oxygen consumption and 2% of body weight)25. The brain is highly sensitive to hypoxia, and in humans it is related to several ageing disorders, such as Alzheimer, Parkinson, and stroke262728. The brain includes both dividing cells, such as astrocytes and glial cells, and post mitotic cells such as neurons that accumulate DNA damage along lifespan.…”

Metabolism and epigenetics in the nervous system: Creating cellular fitness and resistance to neuronal death in neurological conditions via modulation of oxygen-, iron-, and 2-oxoglutarate-dependent dioxygenases

“…Indeed, initial studies from our laboratory over 15 years ago suggested that the broad, salutary effects of the iron chelator, desferoxamine, could be attributed to inhibition of the HIF PHDs and suppression of proline hydroxylation of specific proteins rather than inhibiting iron catalyzed generation of free radicals. Since then, we have used selective chemical tools, peptide inhibitors, and short interfering RNAs to demonstrate that HIF PHD1 is a critical target for neuroprotection in neurons (Aleyasin et al, 2015; Aminova et al, 2008; Karuppagounder and Ratan, 2012; Karuppagounder et al, 2013; Siddiq et al, 2005; Siddiq et al, 2009; Speer et al, 2013; Zaman et al, 1999). …”