Hydrocephalus is a devasting disease for which there is no pharmaceutical treatment. Currently the standard of care involves brain surgery – most usually the placement of a shunt to drain excess cerebrospinal fluid (CSF) from the brain to another area of the body. However, shunts routinely fail for a variety of reasons including infection, blockage and equipment malfunction predisposing the patient to multiple brain surgeries. While pediatric hydrocephalus is perhaps the most recognizable form, there are multiple causes of this condition in older children and adults including traumatic brain injury, stroke, infection. Regardless of the precipitating factors, there is an enlargement of the cerebral ventricles and an excess of CSF in the brain. It is our hypothesis that pharmaceuticals that could decrease CSF production on an as-needed basis would be helpful in treating most forms of hydrocephalus. Rational drug design for such potential treatments is based on a more detailed understanding of the production of CSF by the choroid plexus epithelium (CPe). The small tissue comprising the choroid plexus produces approximately 500 ml of CSF per day, the composition of which varies according to physiological, diurnal, and pathophysiological influences.

In a genetic rat model of hydrocephalus, we have shown that antagonists of the transient receptor potential vanilloid 4 (TRPV4) channel ameliorate the development of hydrocephalus, implicating this channel as a key component of CSF production.  Preliminary studies indicate that TRPV4 antagonists are also effective in rodent models of post hemorrhagic and post traumatic hydrocephalus.  In addition to pre-clinical animal models, we use a human CPe cell model, the HIBCPP (human choroid plexus papilloma) to identify the transepithelial electrolyte and fluid fluxes that occur in response to TRPV4 stimulation. Ussing-style electrophysiology combined with imaging, qRT-PCR and western blotting, have shown that the HIBCPP cells form a moderately tight barrier epithelium consistent with the blood-CSF barrier and express important transporters found in the native epithelium with the correct polarization.  Addition of a TRPV4 agonist causes a multicomponent change in transepithelial electrolyte flux as well as a substantial but reversible change in transepithelial permeability. The TRPV4-mediated electrolyte flux appears to result from secondary activation of multiple transport proteins stimulated in response to the TRPV4-mediated influx of Ca²⁺ and Na⁺ and is a complex mixture of movement of both cations and anions.  This flux is accompanied by a statistically significant secretory movement of fluid in response to the TRPV4 agonist.  Although in vivo the choroid plexus is one of the most secretory epithelia in the body, the degree of fluid secretion by this cell line is unique. The HIBCPP cell line is being used to dissect pathways involved in CSF production.  Our results have uncovered unexpected levels of fluid movement in response to TRPV4 stimulation that can inform the role of opposing electrolyte movements and electroneutral transporters that are difficult to measure using electrophysiological techniques.