Title:Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities
Volume: 16
Issue: 10
Author(s): Amalia Merelli, Julio César García Rodríguez, Jaume Folch, Marcelo R. Regueiro, Antoni Camins and Alberto Lazarowski*
Affiliation:
- INFIBIOC-FFyB-UBA-Buenos, Aires,Argentina
Keywords:
Neurodegeneration, HIF-1, MDR-1, refractory epilepsy, Neuro-EPO, neuroprotection.
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
imbalance, 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
processes 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 nasal administration of pharmacological doses of Neuro-EPO, inducing not only
neuroprotection, but eventually, neurorepair as well.
