Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities

Abstract

Neurodegeneration (NDG) is linked with the progressive loss of neural function with intellectual and/or motor impairment. Several diseases affecting older individuals, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Parkinson's disease, stroke, Multiple Sclerosis and many others, are the most relevant disorders associated with NDG. Since other pathologies such as refractory epilepsy, brain infections, or hereditary diseases such as “neurodegeneration with brain iron accumulation”, also lead to chronic brain inflammation with loss of neural cells, NDG can be said to affect all ages. Owing to an energy and/or oxygen supply imbal-ance, different signaling mechanisms including MAPK/PI3K-Akt signaling pathways, glutamatergic synapse formation, and/or translocation of phosphatidylserine, might activate some central executing mechanism common to all these pathologies and also related to oxidative stress. Hypoxia inducible factor 1-α (HIF-1α) plays a twofold role through gene activation, in the sense that this factor has to “choose” whether to protect or to kill the affected cells. Most of the afore-mentioned process-es follow a protracted course and are accompanied by progressive iron accumulation in the brain. We hypothesize that the neuroprotective effects of iron chelators are acting against the generation of free radicals derived from iron, and also induce sufficient -but not excessive- activation of HIF-1α, so that only the hypoxia-rescue genes will be activated. In this regard, the expression of the erythropoietin receptor in hypoxic/inflammatory neurons could be the cellular “sign” to act upon by the na-sal administration of pharmacological doses of Neuro-EPO, inducing not only neuroprotection, but eventually, neurorepair as well

Potential role of iron in repair of inflammatory demyelinating lesions

“…HIF-2α is known to play an important role in regulation of iron homeostasis, including iron absorption (46,47). Further more, HIF-2α also has essential roles in the CNS, including in developmental myelination, and has been investigated for potential therapeutics in neurodegenerative disorders (48)(49)(50). In our lesions, however, we saw no temporal correlation between HIF-2α levels and DMT1 (Supplemental Figure 3A).…”

Propofol Attenuates Hypoxia-Induced Inflammation in BV2 Microglia by Inhibiting Oxidative Stress and NF-κB/Hif-1α Signaling

“…Microglia are the primary neuroimmune cells participating in surveillance and defense, first sensing pathophysiological changes in the brain, and triggering subsequent cascade reaction [1][2][3]22]. Hypoxia contributes to many central systemic diseases, such as stroke, neonatal hypoxic-ischemic encephalopathy, Alzheimer's disease, Parkinson's disease, vascular dementia, and epilepsy [23][24][25][26]. Hypoxia leads to activation of M1 microglia, which mainly secrete neurotoxic substances such as proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and ROS [27,28].…”

Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders

“…It is a basic helix-loop-helix PAS domain containing protein and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. ( Merelli et al, 2018 ) ( Yeo, 2019 ) HO-1 Heme-Oxygenase-1: it catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2.…”