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

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