Abstract
Background: Cerebrospinal fluid (CSF) secretion can be targeted to reduce elevated intracranial pressure (ICP). Sodium-potassium-chloride cotransporter 1 (NKCC1) antagonism is used clinically. However, supporting evidence is limited. The transient receptor potential vanilloid-4 (TRPV4) channel may also regulate CSF secretion and ICP elevation. We investigated whether antagonism of these proteins reduces CSF secretion. Methods: We quantified CSF secretion rates in male Wistar rats. The cerebral aqueduct was blocked with viscous mineral oil, and a lateral ventricle was cannulated. Secretion rate was measured at baseline and after antagonist administration. Acetazolamide was administered as a positive control to confirm changes in CSF secretion rates. Results: Neither NKCC1, nor TRPV4 antagonism altered CSF secretion rate from baseline, n = 3, t(2) = 1.14, p = 0.37, and n = 4, t(3) = 0.58, p = 0.6, respectively. Acetazolamide reduced CSF secretion by ~50% across all groups, n = 7, t(6) = 4.294, p = 0.005. Conclusions: Acute antagonism of NKCC1 and TRPV4 proteins at the choroid plexus does not reduce CSF secretion in healthy rats. Further investigation of protein changes and antagonism should be explored in neurological disease where increased CSF secretion and ICP are observed before discounting the therapeutic potential of protein antagonism at these sites.
Highlights
Intracranial pressure (ICP) elevation is reported in several neurological conditions including hydrocephalus [1,2], idiopathic intracranial hypertension [3], traumatic brain injury [4,5,6], subarachnoid haemorrhage [7,8,9], and stroke [10,11,12,13,14,15]
A recent preclinical study found that chronic transient receptor potential vanilloid-4 (TRPV4) antagonism effectively ameliorates symptoms of hydrocephalus in a genetic model of the disease [55]. These findings suggest that TRPV4 antagonism could be a novel target for reducing intracranial pressure (ICP) rise in neurological disease or injury
Our study was conducted in rats in the absence of neurological disease or injury; we cannot dismiss the possibility that TRPV4 antagonism has different effects on Cerebrospinal fluid (CSF) secretion under pathological conditions
Summary
Intracranial pressure (ICP) elevation is reported in several neurological conditions including hydrocephalus [1,2], idiopathic intracranial hypertension [3], traumatic brain injury [4,5,6], subarachnoid haemorrhage [7,8,9], and stroke [10,11,12,13,14,15]. A recent preclinical study found that chronic TRPV4 antagonism effectively ameliorates symptoms of hydrocephalus (cranial expansion and ventriculomegaly) in a genetic model of the disease [55] These findings suggest that TRPV4 antagonism could be a novel target for reducing ICP rise in neurological disease or injury. The intention of this study was to build an evidence base to support the role of NKCC1 and TRPV4 as targets for managing CSF secretion before investigating their therapeutic potential for managing ICP in neurological disease and. The intention of this study was to build an evidence base to support the role of NKCC1 and TRPV4 as targets for managing CSF secretion before investigating their therapeutic potential for managing ICP in neurological d3isoefa1s3e and injury.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
