408 - Treatment of Existing Posthemorrhagic Hydrocephalus with a Novel Drug Cocktail in Rats

Poster Number: 408
Publication Number: 408.236

Timothy Heck, Johns Hopkins Children's Center, Glen Burnie, MD, United States; Sana Kamboj, Department of Neurosurgery—Johns Hopkins School of Medicine, Baltimore, MD, United States; Aliyah Allick, Johns Hopkins University, Baltimore, Virgin Islands, United States; Lauren L. Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins University, Baltimore, MD, United States

Background: Treatment of existing posthemorrhagic hydrocephalus of prematurity (PHHP) remains challenging.  In a subset of preterm neonates with intraventricular hemorrhage (IVH), spontaneous recovery of cerebrospinal fluid (CSF) dynamics occurs, suggesting potential for restoration.

Objective: We hypothesize PHHP persists due to a self-propagating chronic inflammation and that neuro-immunomodulatory treatment could eliminate elevated intracranial pressure (ICP). Melatonin (MLT) may potentiate Roxadustat (ROX), a member of a new drug class of oral prolyl hydroxylase domain inhibitors, via Sirtuin-1. We tested a cocktail regimen of Roxadustat plus Melatonin in an established rat model of existing PHHP.

Design/Methods: PHHP was induced using bilateral intracerebroventricular injection of littermate lysed red blood cells on postnatal day 1 (P1) in rats of both sexes exposed prenatally to chorioamnionitis. On P10 (term equivalent) or P21 (toddler), PHHP rats were randomly allocated to receive 10 days of ROX+MLT or vehicle intraperitoneally. Observers were masked to treatment. Intra-aural distance (surrogate head circumference) was measured. Cisterna magna opening pressure (OP) was measured at P21 or P30 (teenager). Digital treadmill analysis at P30 was used to assess gait. Normality was tested with Shapiro-Wilk. Differences between groups were compared using appropriate parametric or nonparametric tests with post-hoc corrections, p< 0.05 considered significant.

Results: Macrocephaly and elevated ICP are hallmarks of PHHP. At P21, PHHP rats had larger heads (n=9-12, p=0.0017) and elevated OP (p < 0.0001) compared to shams. In another cohort, at P30 vehicle-treated PHHP rats (n=13) had larger heads compared to shams (n=22) and higher OP (both p< 0.0001). Notably, ROX+MLT-treated PHHP rats (n=11) had smaller heads compared to vehicle-treated PHHP rats (p=0.02) and lower ICP (p=0.04). Head size and ICP for ROX+MLT-treated PHHP rats did not differ from shams. ROX+MLT treatment P21-P30 also normalized number of steps (p=0.003), ataxia (p=0.04), paw area (p=0.04) and maximal paw pressure (p=0.002).Conclusion(s): CSF dynamics reflect choroid plexus secretion, ependymal motile cilia propulsion and glymphatic system reabsorption of CSF- components all vulnerable to chronic inflammation, exacerbated by preterm IVH. These early results suggest an oral drug cocktail may effectively treat existing PHHP, potentially reducing lifetime shunt-dependence, and relieve associated deficits, such as cerebral palsy.