TRPV4 Activation ‐ Implications in Hydrocephalic Neurodegenerative Disease

Abstract

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and traumatic brain injury, often share similar pathologies, one of which is hydrocephalus. Hydrocephalus is characterized by an imbalance in cerebrospinal fluid (CSF) production and/or reabsorption or by a blockage in the CSF circulation resulting in enlarged ventricles and an increase in brain hydrostatic pressure leading to neuronal destruction. The choroid plexus (CP) is the main producer of CSF and is composed of a high resistance barrier epithelium that surrounds a network of capillaries. The CP epithelium regulates the transport of ions and water between the ventricles and capillaries, thus controlling the production of CSF. Transient Receptor Potential Vanilloid‐4 (TRPV4) is a mechano‐ and osmo‐sensitive, cation channel present in CP epithelia. TRPV4 activation leads to an influx of calcium, which can stimulate calcium activated ion channels leading to the potential for significant transepithelial ion flux. If TRPV4 is overstimulated, it is possible that excess ion movement can cause an increase in CSF volume, resulting in hydrocephalus. Current research in our laboratory has shown that treatment with a TRPV4 antagonist ameliorates hydrocephalus in the Wpk rodent model. We have also shown that TRPV4 expression is increased in the late‐stage hydrocephalic animal compared to normal. TRPV4 can be activated through a number of stimuli, including physical means osmotic changes, increases in temperature and chemical activators, such as cytokines and inflammatory mediators. In particular, the latter activators can be seen in the symptomologies of neurodegenerative diseases exhibiting hydrocephalus. Utilizing a high resistance porcine choroid plexus (PCP‐R) cell line, we investigated the effects of various cytokines, inflammatory mediators, and inflammation pathways on TRPV4 activity using immunohistochemistry and electrophysiology techniques. We found that pro‐inflammatory cytokines, such as Tumor Necrosis Factor (TNF)‐α and interleukin (IL)‐1β, had no effect on TRPV4 stimulated ion flux in vitro; pro‐inflammatory mediators, arachidonic acid and its metabolite 5,6‐epoxyeicosatrienoic acid (EET), had inhibitory effects. Furthermore, the hormone epinephrine, used to combat inflammatory anaphylactic reactions, potentiated TRPV4 activity. Immunofluorescence of the kinase SPAK, which plays a role in Nuclear Factor (NF)‐κB – dependent inflammation and epithelial barrier function, was increased in the CP of hydrocephalic rats compared to the wild type, and inhibitors of NF‐kB altered TRPV4‐mediated ion flux. Together these data imply that selected components of an inflammatory response can play a role in TRPV4 activation and can potentially contribute to the subsequent development of hydrocephalus.Support or Funding InformationDepartment of Defense office of the Congressionally Directed Medical Research Programs (CDMRP) and an Indiana Clinical and Translational Sciences AwardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.