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TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus
Alexandra E. Hochstetler, Hillary M. Smith, Daniel C. Preston, Makenna M. Reed, Paul R. Territo, Joon W. Shim, Daniel Fulkerson, Bonnie L. Blazer-Yost
Alexandra E. Hochstetler, Hillary M. Smith, Daniel C. Preston, Makenna M. Reed, Paul R. Territo, Joon W. Shim, Daniel Fulkerson, Bonnie L. Blazer-Yost
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Research Article Neuroscience Therapeutics

TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus

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Abstract

Hydrocephalus is a serious condition that impacts patients of all ages. The standards of care are surgical options to divert, or inhibit production of, cerebrospinal fluid; to date, there are no effective pharmaceutical treatments, to our knowledge. The causes vary widely, but one commonality of this condition is aberrations in salt and fluid balance. We have used a genetic model of hydrocephalus to show that ventriculomegaly can be alleviated by inhibition of the transient receptor potential vanilloid 4, a channel that is activated by changes in osmotic balance, temperature, pressure and inflammatory mediators. The TRPV4 antagonists do not appear to have adverse effects on the overall health of the WT or hydrocephalic animals.

Authors

Alexandra E. Hochstetler, Hillary M. Smith, Daniel C. Preston, Makenna M. Reed, Paul R. Territo, Joon W. Shim, Daniel Fulkerson, Bonnie L. Blazer-Yost

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Figure 8

TRPV4 activation elicits functional sodium and calcium influx into ex vivo rat choroid plexus.

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TRPV4 activation elicits functional sodium and calcium influx into ex vi...
(A) Ex vivo choroid plexus was incubated in Fluo-4 calcium indicator dye to study calcium influx into the epithelial cells. Ionomycin (100 μM) was used as a positive control for calcium influx, and GSK1016790A (3 nM) was used to agonize TRPV4. TRPV4 activation generated a qualitative increase in fluorescent signal, consistent with allowing calcium influx into the cells. (B) Ex vivo choroid plexus was incubated in CoroNa Green Sodium indicator dye to study sodium influx into the epithelial cells. Nystatin (100 μM) was used as a positive control for sodium influx, and GSK1016790A (3 nM) was used to agonize TRPV4. TRPV4 activation generated a qualitative increase in fluorescent signal, consistent with allowing sodium influx into the cells. TRPV4, transient receptor potential vanilloid 4; GSK, GSK1016790A. Original magnification, 40×.

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