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

Abstract

Background A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology. Methods CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport. Results Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted 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. Conclusions Together, our data reveal that a serum lipid 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 brain water accumulation.

Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production

“…which, taken together with the well-established SPAK-dependent modulation of NKCC1 activity [56,76,84], provide a potential coupling between the elevated androgenic tone observed in IIH patients and elevated NKCC1-mediated CSF secretion rate. The observed increase in NKCC1 activity in testosterone-treated rats therefore offers a mechanistic explanation for the increased CSF flow observed in these rats.…”

“…However, the rats were not controlled for their oestrous cycle in this study, which may introduce cycle-dependent changes in choroid plexus that may mask testosterone-mediated changes in functionality and is thus considered a limitation to the study. NKCC1 hyperactivity has previously been demonstrated as a regulator of CSF production in another condition of disordered CSF dynamics, i.e., posthemorrhagic hydrocephalus [50, 56, 76], likely occurring with activation of the SPS1-related proline/alanine-rich kinase (SPAK) [56, 76], which is highly expressed in the choroid plexus [78]. The androgen receptor, a nuclear receptor targeted by testosterone [79], is also functionally expressed in the rodent choroid plexus [78, 80, 81].…”

“…The androgen receptor, a nuclear receptor targeted by testosterone [79], is also functionally expressed in the rodent choroid plexus [78, 80, 81]. Androgens induce expression of SPAK [82] and modulate NKCC1 activity [83], which, taken together with the well-established SPAK-dependent modulation of NKCC1 activity [56, 76, 84], provide a potential coupling between the elevated androgenic tone observed in IIH patients and elevated NKCC1-mediated CSF secretion rate. The observed increase in NKCC1 activity in testosterone-treated rats therefore offers a mechanistic explanation for the increased CSF flow observed in these rats.…”

“…To determine if the elevated testosterone modulated the rate of CSF secretion, the LI-COR imaging system was used to acutely assess the CSF flow in testosterone-treated female Wistar rats. This experimental approach relies on injection of a fluorescent dye into the lateral ventricle of the anaesthetized rat, after which the rat is swiftly transferred to the whole animal fluorescent reader and the fluorescence dispersion rate obtained as a proxy for the CSF secretion rate [51,[54][55][56] (Fig. 5A).…”

NLRP3-dependent lipid droplet formation contributes to posthemorrhagic hydrocephalus by increasing the permeability of the blood–cerebrospinal fluid barrier in the choroid plexus

“…Adjacent CPECs are bound by tight junctions that form the B-CSFB 6 , but few studies have focused on their function in PHH. CSF hypersecretion was recently demonstrated to be influenced by the activation of ion transporters (NKCC1 and Na + / K + -ATPase) [7][8][9] , and it plays an important role in the pathogenesis of hydrocephalus after ICH-IVH.…”