Erythropoietin Improves Atrophy, Bleeding and Cognition in the Newborn Intraventricular Hemorrhage

Abstract

The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most devastating complications of prematurity. The short-and long-term neurodevelopmental consequences after severe GM-IVH are a major concern for neonatologists. These kids are at high risk of psychomotor alterations and cerebral palsy; however, therapeutic approaches are limited. Erythropoietin (EPO) has been previously used to treat several central nervous system complications due to its role in angiogenesis, neurogenesis and as growth factor. In addition, EPO is regularly used to reduce the number of transfusions in the preterm infant. Moreover, EPO crosses the blood-brain barrier and EPO receptors are expressed in the human brain throughout development. To analyze the role of EPO in the GM-IVH, we have administered intraventricular collagenase (Col) to P7 mice, as a model of GM-IVH of the preterm infant. After EPO treatment, we have characterized our animals in the short (14 days) and the long (70 days) term. In our hands, EPO treatment significantly limited brain atrophy and ventricle enlargement. EPO also restored neuronal density and ameliorated dendritic spine loss. Likewise, inflammation and small vessel bleeding were also reduced, resulting in the preservation of learning and memory abilities. Moreover, plasma gelsolin levels, as a feasible peripheral marker of GM-IVHinduced damage, recovered after EPO treatment. Altogether, our data support the positive effect of EPO treatment in our preclinical model of GM-IVH, both in the short and the long term.

Germinal Matrix-Intraventricular Hemorrhage of the Preterm Newborn and Preclinical Models: Inflammatory Considerations

“…This resembles observed alterations in patients, since white matter is severely affected by GM-IVH and it is also extremely sensitive to inflammation and oxidative stress [123]. Increased neutrophil infiltration [107], increased microglia and astrocyte burdens [109,111,112,125,130,142], gliosis and glial scarring are commonly observed in the periventricular area [89,125,143]. However, increased microglia burden is also observed in brain regions distant from the lesion site, such as the cortex [32,107] or the hippocampus [144], supporting an overall inflammatory response that affects the whole brain [123].…”

“…↑ Reactive gliosis, microglia and astrocyte burdens [32,112,[141][142][143][144]. ↑ Proinflammatory cytokines [145].…”

“…Whereas some differences might be observed when the etiology and experimental approaches are compared, as described in adult models [154], the neuroinflammatory response seems to be reproducible in GM-IVH models. Interestingly, while an overall exacerbated inflammatory response is observed after local lesions [32,130,142] or systemic glycerol administration [63,108] it is noteworthy that pharmacological depletion of microglia before neonatal stroke to P7 rats, significantly increases lesions and the incidence of intraparenchymal hemorrhage. Activated microglia become an important source of TGFβ1 in the injured neonatal brain, that contributes to neurovascular protection, serves as a survival factor for cerebral capillaries and contributes to the stability of the BBB [58].…”

The Effect of Erythropoietin and Its Derivatives on Ischemic Stroke Therapy: A Comprehensive Review

“…In an early postnatal hyperoxia model, EPO had pro-myelinating effects and improved cognition in adolescent and adult rats ( Dewan et al, 2020 ). In a model of germinal matrix-intraventricular hemorrhage (GM-IVH) of the preterm infant, EPO restored the neuronal density, ameliorated dendritic spine loss, and reduced inflammation and small vessel bleeding, contributing to the preservation of learning and memory abilities ( Hierro-Bujalance et al, 2020 ). Recently, using a constitutively expressing transgenic mouse line, a study demonstrated that EPO stimulated the hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice, contributing to improved cognitive behaviors ( Khalid et al, 2021 ).…”

Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage

“…Animal experiments have shown that erythropoietin exerts its neuroprotective effects by reducing inflammation, oxidative stress, and apoptosis and by promoting the regeneration of neuronal stem cells and blood vessels [ 16 – 21 ]. Erythropoietin treatment had positive effects on short- and long-term neurological outcomes in a preclinical model of IVH [ 22 ], and some observational clinical studies also showed that erythropoietin treatment may improve neurodevelopmental outcomes in preterm infants with IVH [ 10 , 23 ]. However, the use of erythropoietin remains controversial with regard to poor outcomes [ 9 ], and both the dose and the course of erythropoietin in preterm infants is uncertain [ 24 , 25 ].…”