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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 L; Barbuskaite, Dagne; Heerfordt, Eva Kjer; Lolansen, Sara Diana; Andreassen, Søren Norge; Rostgaard, Nina; Olsen, Markus Harboe; Norager, Nicolas H; Capion, Tenna; Rath, Martin Fredensborg; Juhler, Marianne; MacAulay, Nanna.
Afiliación
  • Toft-Bertelsen TL; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
  • Barbuskaite D; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
  • Heerfordt EK; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
  • Lolansen SD; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
  • Andreassen SN; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
  • Rostgaard N; Department of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Olsen MH; Department of Neuroanaesthesiology, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Norager NH; Department of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Capion T; Department of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Rath MF; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
  • Juhler M; Department of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • MacAulay N; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Fluids Barriers CNS ; 19(1): 69, 2022 Sep 06.
Article en En | MEDLINE | ID: mdl-36068581
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hemorragia Subaracnoidea / Hidrocefalia Límite: Animals Idioma: En Revista: Fluids Barriers CNS Año: 2022 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hemorragia Subaracnoidea / Hidrocefalia Límite: Animals Idioma: En Revista: Fluids Barriers CNS Año: 2022 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido