Preclinical Testing of TRPV4 Antagonists for the Treatment of Hydrocephalus

Abstract

Cerebrospinal fluid (CSF) is a crucial component of the central nervous system that acts both mechanically and immunologically to support and protect the brain and spinal cord. Absorption and secretion of CSF must be properly maintained to achieve homeostasis. Some diseases, particularly hydrocephalus, experience an accumulation of CSF leading to an excess due to either overproduction or inadequate reabsorption. A small number of treatments are available to overcome this accumulation of CSF, all of which involve invasive surgical procedures that come with high risk and low success rates. The need for alternative treatments leads to a closer look at the choroid plexus, which consists of epithelial cells surrounding a fenestrated capillary network and produces a large portion of the CSF. This research looks specifically at the Transient Receptor Potential Vanilloid 4 (TRPV4), a non‐specific cation channel found in many secretory epithelia. When activated, TRPV4 allows an influx of Ca2+ which leads to downstream intracellular signaling and activation of Ca2+‐activated ion channels. The Wpk rat model, which contains a single point mutation in the TMEM67 gene coding for Mecklin, one of the proteins responsible for the Meckel‐Gruber Syndrome, was used to study possible treatments. Rats that are homozygous recessive for the TMEM67 gene develop a severe form of hydrocephalus that if, left untreated, will result in death by postnatal day 21 (P21). This rat model is analogous to pediatric hydrocephalus in humans. We have used the model to test a TRPV4 antagonist, RN1734, as a possible treatment of hydrocephalus. At P7, the animals received an MRI to measure the volume of the brain ventricles. Subsequently, the animals received daily intraperitoneal injections of the RN1734 through P14. At P15, the animals received a second MRI to observe changes over the course of the treatment. The animals were sacrificed on P15, and their brains, kidneys, and weights were collected. Upon sacrifice, homozygous animals are significantly smaller in body weight than their wild‐type counterparts. The brain weights of the vehicle treated homozygous and the wild‐type animals were not significantly different, however, the homozygous animals treated with the RN compound weighed statistically less than the wild‐type animals. Ventricular volume measurements by MRI revealed that the RN compound caused no effects on normal ventricular growth that occurred from day 7 through 14 in wild‐type and heterozygous animals, but it stopped the substantial ventricular enlargement that occurred over this time period in the homozygous animals. The successful results of the RN1734 treatment in the homozygous animals suggest TRPV4 antagonists for a potential pharmaceutical development for treating hydrocephalus.Support or Funding InformationHydrocephalus Association and Department of Defense Office of the Congressionally Directed Medical Research Programs (CDMRP).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.