Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats.

Shenandoah Robinson,Fatu S Conteh,Frances J Northington,Jessie R Maxwell,Stephen Jett,Jessie C Newville,Nagat El Demerdash,Akosua Y Oppong,Tracylyn R Yellowhair,Christine L Shrock,Lauren L Jantzie

doi:10.3389/fncel.2018.00322

Abstract

Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a global challenge. Early preterm infants (<32 weeks gestation), particularly those exposed to chorioamnionitis (CAM), are prone to intraventricular hemorrhage (IVH) and PHHP. We established an age-appropriate, preclinical model of PHHP with progressive macrocephaly and ventriculomegaly to test whether non-surgical neonatal treatment could modulate PHHP. We combined prenatal CAM and postnatal day 1 (P1, equivalent to 30 weeks human gestation) IVH in rats, and administered systemic erythropoietin (EPO) plus melatonin (MLT), or vehicle, from P2 to P10. CAM-IVH rats developed progressive macrocephaly through P21. Macrocephaly was accompanied by ventriculomegaly at P5 (histology), and P21 (ex vivo MRI). CAM-IVH rats showed impaired performance of cliff aversion, a neonatal neurodevelopmental test. Neonatal EPO+MLT treatment prevented macrocephaly and cliff aversion impairment, and significantly reduced ventriculomegaly. EPO+MLT treatment prevented matted or missing ependymal motile cilia observed in vehicle-treated CAM-IVH rats. EPO+MLT treatment also normalized ependymal yes-associated protein (YAP) mRNA levels, and reduced ependymal GFAP-immunolabeling. Vehicle-treated CAM-IVH rats exhibited loss of microstructural integrity on diffusion tensor imaging, which was normalized in EPO+MLT-treated CAM-IVH rats. In summary, combined prenatal systemic inflammation plus early postnatal IVH caused progressive macrocephaly, ventriculomegaly and delayed development of cliff aversion reminiscent of PHHP. Neonatal systemic EPO+MLT treatment prevented multiple hallmarks of PHHP, consistent with a clinically viable, non-surgical treatment strategy.

Highlights

Posthemorrhagic hydrocephalus of prematurity (PHHP) is a severe form of acquired symptomatic hydrocephalus
No rats from the three control groups became symptomatic from injections, while 4/24 (17%) of CAM-intraventricular hemorrhage (IVH) rats that initially survived required euthanasia prior to their targeted endpoint due to progressive macrocephaly accompanied by lethargy and spastic movements
Was confirmed on post-mortem examination, and these animals were excluded from further analyses

Summary

Introduction

Posthemorrhagic hydrocephalus of prematurity (PHHP) is a severe form of acquired symptomatic hydrocephalus. Of surviving early preterm infants with severe IVH, 50–60% will exhibit ventriculomegaly on head ultrasound (HUS) during the newborn admission (Alan et al, 2012; Romero et al, 2015), 20–30% will develop symptomatic hydrocephalus that requires temporary treatment (Alan et al, 2012; Radic et al, 2015), and 16–20% will require permanent intervention (Alan et al, 2012; Radic et al, 2015; Romero et al, 2015). The need for safe, effective, economical, non-surgical treatment of PHHP cannot be over-stated

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Discussion

Conclusion