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

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-IVH-induced 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.

Transcriptional correlates of the pathological phenotype in a Huntington's disease mouse model.

Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.

Cognitive Impairment and Brain and Peripheral Alterations in a Murine Model of Intraventricular Hemorrhage in the Preterm Newborn.

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) remains a serious complication in the preterm newborn. The significant increase of survival rates in extremelye preterm newborns has also contributed to increase the absolute number of patients developing GMH-IVH. However, there are relatively few available animal models to understand the underlying mechanisms and peripheral markers or prognostic tools. In order to further characterize central complications and evolution of GMH-IVH, we injected collagenase intraventricularly to P7 CD1 mice and assessed them in the short (P14) and the long term (P70). Early complications at P14 included ventricle enlargement, increased bleeding, and inflammation. These alterations were maintained at P70, when increased tau phosphorylation and decreased neurogenesis were also observed, resulting in impaired learning and memory in these early adult mice. We additionally analyzed peripheral blood biomarkers in both our mouse model and preterm newborns with GMH-IVH. While MMP9 levels were not significantly altered in mice or newborns, reduced gelsolin levels and increased ubiquitin carboxy-terminal hydrolase L1 and tau levels were detected in GMH-IVH patients at birth. A similar profile was observed in our mouse model after hemorrhage. Interestingly, early changes in gelsolin and carboxy-terminal hydrolase L1 levels significantly correlated with the hemorrhage grade in newborns. Altogether, our data support the utility of this animal model to reproduce the central complications and peripheral changes observed in the clinic, and support the consideration of gelsolin, carboxy-terminal hydrolase L1, and tau as feasible biomarkers to predict the development of GMH-IVH.

Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring.

BACKGROUND: Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited. METHODS: Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term. RESULTS: Central complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system. CONCLUSIONS: Our data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.