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 secret...
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| Format: | Article |
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BMC
2022-09-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-022-00361-9 |
| _version_ | 1818064823373529088 |
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| author | Trine L. Toft-Bertelsen Dagne Barbuskaite Eva Kjer Heerfordt Sara Diana Lolansen Søren Norge Andreassen Nina Rostgaard Markus Harboe Olsen Nicolas H. Norager Tenna Capion Martin Fredensborg Rath Marianne Juhler Nanna MacAulay |
| author_facet | Trine L. Toft-Bertelsen Dagne Barbuskaite Eva Kjer Heerfordt Sara Diana Lolansen Søren Norge Andreassen Nina Rostgaard Markus Harboe Olsen Nicolas H. Norager Tenna Capion Martin Fredensborg Rath Marianne Juhler Nanna MacAulay |
| author_sort | Trine L. Toft-Bertelsen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T14:42:07Z |
| format | Article |
| id | doaj.art-12b67afbfdf54caabe6b5c927c79222c |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-12-10T14:42:07Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-12b67afbfdf54caabe6b5c927c79222c2022-12-22T01:44:39ZengBMCFluids and Barriers of the CNS2045-81182022-09-0119111710.1186/s12987-022-00361-9Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1Trine L. Toft-Bertelsen0Dagne Barbuskaite1Eva Kjer Heerfordt2Sara Diana Lolansen3Søren Norge Andreassen4Nina Rostgaard5Markus Harboe Olsen6Nicolas H. Norager7Tenna Capion8Martin Fredensborg Rath9Marianne Juhler10Nanna MacAulay11Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - RigshospitaletDepartment of Neuroanaesthesiology, Neuroscience Centre, Copenhagen University Hospital - RigshospitaletDepartment of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - RigshospitaletDepartment of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - RigshospitaletDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - RigshospitaletDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenAbstract 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.https://doi.org/10.1186/s12987-022-00361-9Transient receptor potential vanilloid 4Choroid plexusLPAMembrane transportIntraventricular hemorrhageIVH |
| spellingShingle | Trine L. Toft-Bertelsen Dagne Barbuskaite Eva Kjer Heerfordt Sara Diana Lolansen Søren Norge Andreassen Nina Rostgaard Markus Harboe Olsen Nicolas H. Norager Tenna Capion Martin Fredensborg Rath Marianne Juhler Nanna MacAulay Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1 Fluids and Barriers of the CNS Transient receptor potential vanilloid 4 Choroid plexus LPA Membrane transport Intraventricular hemorrhage IVH |
| title | Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1 |
| title_full | Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1 |
| title_fullStr | Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1 |
| title_full_unstemmed | Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1 |
| title_short | Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1 |
| title_sort | lysophosphatidic acid as a csf lipid in posthemorrhagic hydrocephalus that drives csf accumulation via trpv4 induced hyperactivation of nkcc1 |
| topic | Transient receptor potential vanilloid 4 Choroid plexus LPA Membrane transport Intraventricular hemorrhage IVH |
| url | https://doi.org/10.1186/s12987-022-00361-9 |
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