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

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Abstract

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.

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Acknowledgements

We thank the animal facility (SEPA) of the University of Cadiz for their technical support and Dr. Alberto Serrano-Pozo and Mr. Guillaume Pagnier for their help reviewing this manuscript. MG-A received funding from Ministerio de Educación, Cultura y Deporte en el marco del Programa Estatal de Promoción del Talento y su Empleabilidad en I+D+i, Subprograma Estatal de Movilidad, del Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016 (PRX16/00246). This study was supported by the National Programme for Research Aimed at the Challenges of Society (BFU 2016-75038-R), financed by the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER), and the Proyectos de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo Junta de Andalucía (P11-CTS-7847).

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Authors and Affiliations

  1. Division of Neonatology, Hospital Universitario Puerta del Mar, Cadiz, Spain

    Antonio Segado-Arenas, Isabel Benavente-Fernandez, Daniel Sanchez-Sotano, Almudena Alonso-Ojembarrena & Simon Lubian-Lopez

  2. Division of Physiology, School of Medicine, Instituto de Investigación Biomédica e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Universidad de Cadiz, Plaza Fragela sn, 4 piso 410, Cadiz, Spain

    Carmen Infante-Garcia, Daniel Sanchez-Sotano, Juan Jose Ramos-Rodriguez & Monica Garcia-Alloza

  3. Salus Infirmorum, Universidad de Cadiz, Cadiz, Spain

    Carmen Infante-Garcia & Juan Jose Ramos-Rodriguez

  4. Division of Pediatrics, Hospital Universitario Puerta del Mar, Ava. Ana de Villa sn, Cadiz, Spain

    Simon Lubian-Lopez

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  1. Antonio Segado-Arenas
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  2. Carmen Infante-Garcia
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Correspondence to Simon Lubian-Lopez or Monica Garcia-Alloza.

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Segado-Arenas, A., Infante-Garcia, C., Benavente-Fernandez, I. et al. Cognitive Impairment and Brain and Peripheral Alterations in a Murine Model of Intraventricular Hemorrhage in the Preterm Newborn. Mol Neurobiol 55, 4896–4910 (2018). https://doi.org/10.1007/s12035-017-0693-1

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  • DOI: https://doi.org/10.1007/s12035-017-0693-1

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