Biology subjects

Lolansen, S. D.

Publications and source records attributed to Lolansen, S. D..

2 recordsLinked to original sources

bioRxiv2022

Lysophosphatidic acid, a CSF marker in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1

A range of neurological pathologies can cause secondary hydrocephalus. For decades, treatment has been limited to surgical CSF diversion, as still no pharmacological options exist due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties. We have now identified phospholipid lysophosphatidic acid (LPA) as a biomarker for posthemorrhagic hydrocephalus (PHH) in patients with subarachnoid hemorrhage (SAH) and mimicked our results in an animal model of intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+, K+, 2Cl- cotransporter (NKCC1) implicated in CSF secretion. Together, our data reveal that a biomarker present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving disturbed brain fluid dynamics.

neuroscience↗

bioRxiv2021

Cerebrospinal fluid formation is controlled by membrane transporters to modulate intracranial pressure

Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Here, we employed experimental rats to demonstrate low osmotic water permeability of the choroid plexus, lack of an osmotic gradient across this tissue, and robust CSF secretion against osmotic gradients. Together, these results illustrate that CSF secretion occurs independently of conventional osmosis, which challenges the existing assumption that CSF production is driven entirely by bulk osmotic forces across the CSF-secreting choroid plexus. Instead, we reveal that the choroidal Na+/K+/Cl- cotransporter NKCC1, Na+/HCO3- cotransporter NBCe2, and Na+/K+-ATPase are actively involved in CSF production and propose a molecular mode of water transport supporting CSF production in this secretory tissue. Further, we demonstrate that inhibition of NKCC1 directly reduces the ICP, illustrating that altered CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.

neuroscience↗