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Effects of a TRPV4 Antagonist on Hydrocephalus in Wpk Rat Model
Author(s) -
Danko Caleb,
Preston Daniel,
Simpson Stefanie,
BlazerYost Bonnie
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1042.4
Subject(s) - hydrocephalus , choroid plexus , cerebrospinal fluid , medicine , endocrinology , anesthesia , surgery , central nervous system
Hydrocephalus is a disease classified by an excess of Cerebrospinal Fluid (CSF) in the brain resulting from a variety of causes. Current treatments for hydrocephalus are limited to invasive surgical procedures that have high risks of failure or infection. The Choroid Plexus (CP) is responsible for production of the CSF, and is found in the lateral, third, and fourth ventricles of the brain. The CP contains a high resistance epithelium that tightly regulates the ionic and water movement during the production of CSF. The Wpk rat model has a single point mutation that induces a ciliopathy in homozygous recessive allele expression leading to hydrocephalus and polycystic kidney disease. The hydrocephalus in the Wpk rat model is a homologue to pediatric hydrocephalus that mimics a rapid progression of the disease, resulting in death of the rats, without intervention, within the first 21 days of life. Considering the tight control of fluid/electrolyte regulation in the CP, we have explored an osmotic‐ and mechano‐sensitive Ca 2+ influx channel the transient receptor potential vanilloid‐4 (TRPV4), as a potential target for pharmaceutical regulation of CSF production. The Wpk rat pups are given a daily, intraperitoneal injection of the TRPV4 antagonist, RN1734 starting on day 7 after birth (P7), continuing through day 14 (P14), with untreated animals receiving a vehicle injection. Body weight is recorded daily with injections calculated for controlled drug doses according to body weight. Wpk rats were humanely euthanized on P15 with measurements taken of the body weight, kidney weight, cranial dimensions, and brain weight. These data were expressed in several parameters to account for the differences in body weight between the hydrocephalic and wild type pups as well as to account for the increase in cystic kidney weight in homozygous animals. Drug treatment had no effect on body weight, head dimensions or behavior of the wild‐type animals. However, in the hydrocephalic animals, head size in both the vertical and horizontal dimension were statistically decreased by antagonist treatment. These relationships were valid even when body weight or anephric body weights were taken into consideration. Likewise the brain weights were statistically lowered by treatment in the hydrocephalic animals. In this genetic model of hydrocephalus, treatment with a TRPV4 antagonist substantially ameliorates the hydrocephalic development suggesting that this class of drugs might be a good target for pharmaceutical development. Support or Funding Information Funding: Hydrocephalus Association Innovator Award; Indiana University Collaborative Research Grant and Indiana Clinical and Translational Sciences Institute CTR Award.