Introduction

The incidence of premature brain injuries (PBI) is rising along with preterm birth, mainly caused by perinatal hypoxia due to immature lung development. PBI is characterized by a reduction in cortical gray and white matter volumes, reduced hippocampal size and increased ventricle size (ventriculomegaly). These alterations in structural brain organization can lead to major life-long neurological dysfunctions such as cerebral palsy, mental retardation and increased risk of temporal lobe epilepsy.

Limited progress has been made in developing therapies to prevent long term neurological disorders caused by PBI. Erythropoietin (Epo), a hypoxia-inducible hormone highly expressed in the brain during embryonic and fetal development, has been shown to be neuroprotective and is a favorable therapeutic target for treating premature neonates.

Our group’s goal is to find neuroprotective strategies in premature brain injury (PBI). For this aim we use a mouse model of neuroprotection in which erythropoietin (Epo) is overexpressed in the brain and in conditional knockout (KO) lines of floxed EpoR mice intercrossed with neural progenitor cells (Nestin-cre), and oligodendrocyte precursor cells (Sox10-cre) mouse lines. We evaluate Epo’s effect on neuronal differentiation, GABAergic maturation, myelination, astrocytic reactivity and angiogenesis under normal (normoxic) conditions and after PBI (hypoxia). We combine in vivo and in vitro approaches, imaging techniques, and electrophysiology to address the mechanisms by which Epo acts on the brain to elicit possible changes in brain metabolism and the interactions between blood vessels, astrocytes, and neurons. Additionally, we evaluate Epo’s effect on neural and oligodendrocyte differentiation.

Our findings should uncover the function of Epo in the maturation of the central nervous system and validate the use of Epo in neonatology to prevent developmental delays and abnormalities caused by perinatal hypoxia.

Figure

Cerebral hypoxic injury caused in juvenile rats (right) after fast ascent to high altitude (Jungfraujoch, 3471 m)