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Author Notes:

Stephen Tomlinson, tomlinss@musc.edu

Ramin Eskandari, eskandar@musc.edu

M.A., D.H., K.M., A.A., S.T. and R.E. designed research; M.A., D.H., T.V., A.S., J.C. and C.G. performed research; M.A., D.H., T.V., K.M., A.S. and J.C. contributed unpublished reagents/analytic tools; M.A., D.H., T.V., A.S., J.C., C.G., R.E. and S.T. analyzed and interpreted data; M.A., D.H., K.M., J.C., S.T. and R.E. wrote the paper. All authors have read and agreed to the published version of the manuscript.

The authors would also like to acknowledge the MUSC Cell and Molecular Imaging Core, supported in part by the Cell and Molecular Imaging Shared Resource, MUSC Cancer Center Support Grant (P30 CA138313), the SC COBRE in Oxidants, Redox Balance, and Stress Signaling (P20 GM103542), the SC COBRE in Digestive and Liver Diseases (P20 GM130457), the MUSC Digestive Disease Core Center (P30 DK123704), the Shared Instrumentation Grants S10 OD018113 and S10 OD028663, and the CNDD Mouse Behavior Phenotyping Core (P20 GM184302).

The authors declare no conflict of interest.

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Research Funding:

This research was funded by the Neurosurgery Research and Education Foundation (NREF) through the AANS/CNS Section on Pediatric Neurological Surgery & NREF 2020-21 Research Fellowship Grant to M.A. It is also funded by grants from the Department of Veterans Affairs (IK6BX005235, 1BX004256, 1RX001141) to S.T., and the National Institutes of Health (NIH) (T32AI132164) to K.M.

Keywords:

  • germinal matrix hemorrhage
  • intraventricular hemorrhage
  • neuroinflammation
  • hydrocephalus
  • periventricular leukomalacia
  • complement

Complement Drives Chronic Inflammation and Progressive Hydrocephalus in Murine Neonatal Germinal Matrix Hemorrhage

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Journal Title:

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Volume:

Volume 24, Number 12

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

Germinal matrix hemorrhage (GMH) is a pathology that occurs in infancy, with often devastating long-term consequences. Posthemorrhagic hydrocephalus (PHH) can develop acutely, while periventricular leukomalacia (PVL) is a chronic sequala. There are no pharmacological therapies to treat PHH and PVL. We investigated different aspects of the complement pathway in acute and chronic outcomes after murine neonatal GMH induced at postnatal day 4 (P4). Following GMH-induction, the cytolytic complement membrane attack complex (MAC) colocalized with infiltrating red blood cells (RBCs) acutely but not in animals treated with the complement inhibitor CR2-Crry. Acute MAC deposition on RBCs was associated with heme oxygenase-1 expression and heme and iron deposition, which was reduced with CR2-Crry treatment. Complement inhibition also reduced hydrocephalus and improved survival. Following GMH, there were structural alterations in specific brain regions linked to motor and cognitive functions, and these changes were ameliorated by CR2-Crry, as measured at various timepoints through P90. Astrocytosis was reduced in CR2-Crry-treated animals at chronic, but not acute, timepoints. At P90, myelin basic protein and LAMP-1 colocalized, indicating chronic ongoing phagocytosis of white matter, which was reduced by CR2-Crry treatment. Data indicate acute MAC-mediated iron-related toxicity and inflammation exacerbated the chronic effects of GMH.

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© 2023 by the authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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