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Author Notes:

R.E, Email: eskandar@musc.edu

S.T, Email: tomlinss@musc.edu

M.A., K.M., A.A., S.T. and R.E. designed research; M.A., K.M., T.V., D.B. and C.C. performed research; M.A., K.M., T.V., C.S. and J.C. contributed unpublished reagents/analytic tools; M.A., K.M., T.V., J.C., C.S., R.E. and S.T. analyzed and interpreted data; M.A., K.M., J.C., S.T. and R.E. wrote the paper.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.

We acknowledge the MUSC Cell and Molecular Imaging Core, which is supported in part by the Cell & 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), and the Shared Instrumentation Grants S10 OD018113 and S10 OD028663.

S.T. is an inventor of a licensed patent for CR2-targeted complement inhibitors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Research Funding:

This work was supported by the Neurosurgery Research and Education Foundation (NREF) through the AANS/CNS Section on Pediatric Neurological Surgery & NREF 2020-21 Research Fellowship Grant to MA. It was also supported by grants from the Department of Veterans Affairs (IK6BX005235, 1BX004256, 1RX001141) to ST, and the National Institutes of Health (NIH) (T32AI132164) to KM.

Keywords:

  • germinal matrix hemorrhage
  • hydrocephalus
  • neuroinflammation
  • complement
  • microglia
  • pediatric

A Role of Complement in the Pathogenic Sequelae of Mouse Neonatal Germinal Matrix Hemorrhage

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Journal Title:

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Volume:

Volume 23, Number 6

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Type of Work:

Article | Final Publisher PDF

Abstract:

Germinal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia, and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed and characterized a mouse model of GMH based on the injection of collagenase into the subventricular zone of post-natal pups and utilized the model to investigate the role of complement in PHH development. The site-targeted complement inhibitor CR2Crry, which binds deposited C3 complement activation products, localized specifically in the brain following its systemic administration after GMH. Compared to vehicle, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Complement inhibition also improved survival and weight gain, and it improved motor performance and cognitive outcomes measured in adolescence. The progression to PHH, neuronal loss, and associated behavioral deficits was linked to the microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Thus, complement plays an important role in the pathological sequelae of GMH, and complement inhibition represents a novel therapeutic approach to reduce the disease progression of a condition for which there is currently no treatment outside of surgical intervention.

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© 2022 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/rdf).
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