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  • Review Article
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Neuroinflammatory pathways and potential therapeutic targets in neonatal post-hemorrhagic hydrocephalus

Pediatric Research volume 97, pages 1345–1357 (2025)Cite this article

Abstract

Background

Post-hemorrhagic hydrocephalus (PHH) is a severe complication in premature infants following intraventricular hemorrhage (IVH). It is characterized by abnormal cerebrospinal fluid (CSF) accumulation, disrupted CSF dynamics, and elevated intracranial pressure (ICP), leading to significant neurological impairments.

Objective

This review provides an overview of recent molecular insights into the pathophysiology of PHH and evaluates emerging therapeutic approaches aimed at addressing its underlying mechanisms.

Methods

Recent studies were reviewed, focusing on molecular and cellular mechanisms implicated in PHH, including neuroinflammatory pathways, immune mediators, and regulatory genes. The potential of advanced technologies such as whole genome/exome sequencing, proteomics, epigenetics, and single-cell transcriptomics to identify key molecular targets was also analyzed.

Results

PHH has been strongly linked to neuroinflammatory processes triggered by the degradation of blood byproducts. These processes involve cytokines, chemokines, the complement system, and other immune mediators, as well as regulatory genes and epigenetic mechanisms. Current treatments, primarily surgical CSF diversion, do not address the underlying molecular pathology. Emerging therapies, such as mesenchymal stem cell-based interventions, show promise in modulating immune responses and mitigating neurological damage. However, concerns about the safety of these novel approaches in neonatal populations and their potential effects on brain development remain unresolved.

Conclusions

Advanced molecular tools and emerging therapies have the potential to transform the treatment of PHH by targeting its underlying pathophysiology. Further research is needed to validate these approaches, enhance their safety profiles, and improve outcomes for infants with PHH.

Impact statement

  1. 1.

    This review elucidates the molecular complexities of post-hemorrhagic hydrocephalus (PHH) by examining specific immune pathways and their impact on disease pathogenesis and progression.

  2. 2.

    It outlines the application of genomic, epigenomic, and proteomic technologies to identify critical molecular targets in PHH, setting the stage for innovative, targeted therapeutic approaches that could improve the outcomes of neonates affected by PHH.

  3. 3.

    It discusses the potential of gene and stem cell therapies in treating PHH, offering non-surgical alternatives and focusing on the underlying neuroinflammatory mechanisms.

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Fig. 1: This figure illustrates the key molecular and cellular components involved in the neuro-inflammatory response in post-hemorrhagic hydrocephalus (PHH) and provides an overview of their physiological impacts.
Fig. 2: This figure proposes the activation mechanisms of NKCC1 in the ChP’s luminal membrane.
Fig. 3: This figure shows the role of the choroid plexus (ChP) in the pathogenesis of acquired hydrocephalus after brain infection or hemorrhage.
Fig. 4: This figure illustrates the role of Aquaporin-4 (AQP4) in brain fluid dynamics.
Fig. 5: Depicted here is the role of the Na-K-Cl cotransporter (NKCC1) in managing PHH via targeted gene therapy in the ChP.

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Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

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Authors and Affiliations

  1. Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH, USA

    Lauren N. Schulz, Michelle Wedemeyer, Jonathan A. Pindrik, Jeffrey R. Leonard & Albert M. Isaacs

  2. Department of Undergraduate Studies, Miami University, Oxford, OH, USA

    Aaron Varghese

  3. Medical Scientist Training Program, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Marie Michenkova & David D. Limbrick Jr

  4. Division of Neurological Surgery, Nationwide Children’s Hospital, Columbus, OH, USA

    Michelle Wedemeyer, Jonathan A. Pindrik, Jeffrey R. Leonard & Albert M. Isaacs

  5. Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA

    Michelle Wedemeyer, Richard K. Wilson, Elaine R. Mardis & Albert M. Isaacs

  6. Department of Neurosurgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Maria Garcia-Bonilla & David D. Limbrick Jr

  7. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA

    James Pat McAllister

  8. Division of Infectious Disease, Nationwide Children’s Hospital, Columbus, OH, USA

    Kevin Cassady

  9. Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA

    Kevin Cassady

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Contributions

L.N.S. conducted the primary literature review and drafted the initial manuscript. A.V. synthesized molecular insights and contributed to the discussion of neuroinflammatory pathways in post-hemorrhagic hydrocephalus. M.M. provided expertise on epigenetic mechanisms and potential therapeutic targets. M.W. assisted with the conceptual framework and contributed to revising and refining the manuscript. J.A.P. and J.R.L. reviewed the clinical implications of neuroinflammation and potential treatments, ensuring relevance to neonatal care. M.G.-B. contributed insights on immune-mediated neuroinflammation. J.P.M. provided guidance on cerebrospinal fluid dynamics in PHH. K.C. reviewed discussions on advanced molecular tools, including transcriptomics and proteomics. R.K.W. and E.R.M. contributed expertise on genomic technologies and their translational applications. D.D.L. provided critical feedback on therapeutic approaches and future directions. A.M.I. conceived the review, coordinated contributions from all authors, and finalized the manuscript for submission. All authors contributed to and approved the final manuscript.

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Correspondence to Albert M. Isaacs.

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Schulz, L.N., Varghese, A., Michenkova, M. et al. Neuroinflammatory pathways and potential therapeutic targets in neonatal post-hemorrhagic hydrocephalus. Pediatr Res 97, 1345–1357 (2025). https://doi.org/10.1038/s41390-024-03733-z

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