Ameliorating Ventriculomegaly in the Wpk Rat Model of Postnatal Hydrocephalus
Authors: Danko Caleb , Preston Daniel , Simpson Stefanie , Territo Paul , Blazer‐Yost Bonnie 
Published: June 2021

In the pediatric population, hydrocephalus is a disease that affects approximately 1:1000 births. This disease has multiple causes that can result in a dysfunction of the homeostatic mechanisms of cerebrospinal fluid (CSF) secretion or absorption, or a blockage of CSF circulation, any of which can lead to an over accumulation of CSF within the ventricles of the brain, resulting in ventriculomegaly. In pediatric patients this results in enlarged cranial dimensions. Current therapeutic treatments for hydrocephalus include ventriculoperitoneal shunt implantation to create an artificial drainage mechanism for the CSF or an endoscopic third ventriculostomy, ablating a portion of the choroid plexus (CP) of the third ventricle. While the current treatment options are effective in treating the ventriculomegaly of hydrocephalus, both pose serious risks to individuals, notably high shunt failure rates and/or ablation of a tissue critical to cerebral homeostasis. The CP epithelium is a critical barrier tissue which forms the blood‐CSF barrier, maintaining a similar function to that of the blood brain barrier. The CP also produces the majority of the CSF. However, the regulatory mechanisms controlling CSF production and composition are poorly defined. Developing a better understanding of these regulatory mechanisms could lead to novel drug treatments for hydrocephalus. The Wpk rat model of Meckel Gruber Syndrome exhibits severe hydrocephalus in the homozygous animals (Wpk −/−) which causes terminal disease by postnatal (P) day 21. The Wpk heterozygous (Wpk +/−) animals exhibit a mild form of hydrocephalus and live to approximately 1 year of age. Previously we reported that treatment with RN1734, an antagonist of the transient receptor potential vanilloid‐4 (TRPV4) channel reduces cranial dimensions of Wpk −/− hydrocephalic rats. TRPV4 is an osmo‐ and mechano‐sensitive Ca2+ influx channel located in the CP epithelium. For the present studies the rats were treated with either RN1734 or a vehicle by daily intraperitoneal injection from P7 through P14. Pre‐treatment MRIs were taken on P7 and post‐treatment MRIs on P15 in order to quantify the volume of the ventricles. Wpk −/− rats treated with RN1734 had a significantly reduced ventricular volume compared to their vehicle treated counterparts. Wild‐type and Wpk +/− rats had reduced ventricular volumes but with a limited number of animals this did not reach statistical significance. These data suggest that TRPV4 plays a role in the production of CSF, and may provide insight into new pharmaceutical targets to treat hydrocephalus.

Support or Funding Information

Hydrocephalus Association Innovator Award; Indiana University Collaborative Research Grant and Indiana Clinical and Translational Sciences Institute CTR Award; Department of Defense Office of the Congressionally Directed Medical Research Programs (CDMRP).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.