Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1
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Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1. / Toft-Bertelsen, Trine Lisberg; Barbuskaite, Dagne; Heerfordt, Eva Kjær; Lolansen, Sara Diana; Andreassen, Søren Norge; Rostgaard, Nina; Olsen, Markus Harboe; Norager, Nicolas H.; Capion, Tenna; Rath, Martin Fredensborg; Juhler, Marianne; MacAulay, Nanna.
In: Fluids and Barriers of the CNS, Vol. 19, No. 1, 69, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1
AU - Toft-Bertelsen, Trine Lisberg
AU - Barbuskaite, Dagne
AU - Heerfordt, Eva Kjær
AU - Lolansen, Sara Diana
AU - Andreassen, Søren Norge
AU - Rostgaard, Nina
AU - Olsen, Markus Harboe
AU - Norager, Nicolas H.
AU - Capion, Tenna
AU - Rath, Martin Fredensborg
AU - Juhler, Marianne
AU - MacAulay, Nanna
N1 - © 2022. The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Transient receptor potential vanilloid 4
KW - Choroid plexus
KW - LPA
KW - Membrane transport
KW - Intraventricular hemorrhage
KW - IVH
KW - SAH
KW - Subarachnoid hemorrhage
KW - Cerebrospinal fluid
KW - Brain water
KW - CHOROID-PLEXUS
KW - COTRANSPORTERS
KW - PATHOGENESIS
KW - PHARMACOLOGY
KW - BUMETANIDE
KW - ONTOLOGY
KW - PATHWAY
KW - CHANNEL
KW - ONLINE
KW - GENES
U2 - 10.1186/s12987-022-00361-9
DO - 10.1186/s12987-022-00361-9
M3 - Journal article
C2 - 36068581
VL - 19
JO - Fluids and Barriers of the CNS
JF - Fluids and Barriers of the CNS
SN - 2045-8118
IS - 1
M1 - 69
ER -
ID: 319359530