TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus

Hochstetler, Alexandra; Smith, Hillary M.; Preston, Daniel; Reed, Makenna; Territo, Paul R.; Shim, Joon W.; Fulkerson, Daniel H.; Blazer‐Yost, Bonnie L.

doi:10.1172/jci.insight.137646

Cited by 34 publications

(65 citation statements)

References 29 publications

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“…We hypothesised that TRPV4 antagonism would reduce CSF secretion, as previous studies of TRPV4 expression sites and ion transport activity have alluded to a regulatory role for the protein in CSF secretion [ 44 , 63 ]. Additionally, chronic TRPV4 antagonism is effective at reducing symptoms of hydrocephalus in rats, a disease characterised by the abnormal accumulation of CSF [ 55 ]. We report that acute antagonist administration did not decrease average CSF secretion rates.…”

Section: Discussionmentioning

confidence: 99%

“…The TRPV4 antagonist, RN1734, in dimethylsulfoxide (DMSO), was administered intraperitoneally as previously described [ 55 ]. Although this method is not the most efficacious route of delivery, it is far less invasive than intraventricular administration and is more clinically relevant.…”

Section: Methodsmentioning

confidence: 99%

“…Although this method is not the most efficacious route of delivery, it is far less invasive than intraventricular administration and is more clinically relevant. We used 10 mg/kg of RN1734 as we expected this dose to produce an adequate response, considering 4 mg/kg is enough to reduce symptoms of hydrocephalus in rats and 5 mg/kg reduces TRPV4 expression in the CNS [ 55 , 56 ]. Further, we checked for changes to CSF secretion rate after administration of DMSO and confirmed that DMSO had no effect.…”

Section: Methodsmentioning

confidence: 99%

“…TRPV4 is also upregulated and activated in brain parenchyma after ischaemic stroke and traumatic brain injury [ 52 , 53 , 54 ]. Further, 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.…”

Section: Introductionmentioning

confidence: 99%

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CSF Secretion Is Not Altered by NKCC1 Nor TRPV4 Antagonism in Healthy Rats

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CSF Secretion Is Not Altered by NKCC1 Nor TRPV4 Antagonism in Healthy Rats

et al. 2021

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“…There is a dire need for therapeutics that can alleviate the burden of hydrocephalus. Hochstetler et al [111] recently reported that antagonists of transient receptor potential vanilloid 4 (TRPV4) channels can ameliorate hydrocephalus in a rat genetic model. Zhang et al [112] developed a novel, potent SPAK kinase inhibitor that regulates brain cation-Cl − cotransporters.…”

Section: Hydrocephalus Treatmentmentioning

confidence: 99%

Brain Barriers and brain fluids research in 2020 and the fluids and barriers of the CNS thematic series on advances in in vitro modeling of the blood–brain barrier and neurovascular unit

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Jones²,

Drewes

2021

Fluids Barriers CNS

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This editorial discusses advances in brain barrier and brain fluid research in 2020. Topics include: the cerebral endothelium and the neurovascular unit; the choroid plexus; the meninges; cerebrospinal fluid and the glymphatic system; disease states impacting the brain barriers and brain fluids; drug delivery to the brain. This editorial also highlights the recently completed Fluids Barriers CNS thematic series entitled, ‘Advances in in vitro modeling of the blood–brain barrier and neurovascular unit’. Such in vitro modeling is progressing rapidly.

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TRPV4: A trigger of pathological RhoA activation in neurological disease

2022

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Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface-localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton.Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4-RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood-brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4-RhoA activation in a range of neurological diseases.

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TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus

Cited by 34 publications

References 29 publications

CSF Secretion Is Not Altered by NKCC1 Nor TRPV4 Antagonism in Healthy Rats

CSF Secretion Is Not Altered by NKCC1 Nor TRPV4 Antagonism in Healthy Rats

Brain Barriers and brain fluids research in 2020 and the fluids and barriers of the CNS thematic series on advances in in vitro modeling of the blood–brain barrier and neurovascular unit

TRPV4: A trigger of pathological RhoA activation in neurological disease

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