Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure
Abstract Background 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 details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely u...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-022-00358-4 |
| _version_ | 1798004496827154432 |
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| author | Eva K. Oernbo Annette B. Steffensen Pooya Razzaghi Khamesi Trine L. Toft-Bertelsen Dagne Barbuskaite Frederik Vilhardt Niklas J. Gerkau Katerina Tritsaris Anja H. Simonsen Sara D. Lolansen Søren N. Andreassen Steen G. Hasselbalch Thomas Zeuthen Christine R. Rose Vartan Kurtcuoglu Nanna MacAulay |
| author_facet | Eva K. Oernbo Annette B. Steffensen Pooya Razzaghi Khamesi Trine L. Toft-Bertelsen Dagne Barbuskaite Frederik Vilhardt Niklas J. Gerkau Katerina Tritsaris Anja H. Simonsen Sara D. Lolansen Søren N. Andreassen Steen G. Hasselbalch Thomas Zeuthen Christine R. Rose Vartan Kurtcuoglu Nanna MacAulay |
| author_sort | Eva K. Oernbo |
| collection | DOAJ |
| description | Abstract Background 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 details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Methods Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus. Results We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na+/K+/2Cl− cotransporter NKCC1, the Na+/HCO3 − cotransporter NBCe2, and the Na+/K+-ATPase, but not on the Na+/H+ exchanger NHE1. We demonstrate that pharmacological modulation of CSF secretion directly affects the ICP. Conclusions CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of 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. |
| first_indexed | 2024-04-11T12:24:42Z |
| format | Article |
| id | doaj.art-5f05e5d9134e47b3a3b4351767140f5a |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-04-11T12:24:42Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-5f05e5d9134e47b3a3b4351767140f5a2022-12-22T04:23:59ZengBMCFluids and Barriers of the CNS2045-81182022-08-0119112510.1186/s12987-022-00358-4Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressureEva K. Oernbo0Annette B. Steffensen1Pooya Razzaghi Khamesi2Trine L. Toft-Bertelsen3Dagne Barbuskaite4Frederik Vilhardt5Niklas J. Gerkau6Katerina Tritsaris7Anja H. Simonsen8Sara D. Lolansen9Søren N. Andreassen10Steen G. Hasselbalch11Thomas Zeuthen12Christine R. Rose13Vartan Kurtcuoglu14Nanna MacAulay15Department of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenInstitute of Physiology, University of ZurichDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Cellular and Molecular Medicine, University of CopenhagenInstitute of Neurobiology, Heinrich Heine University DüsseldorfDepartment of Cellular and Molecular Medicine, University of CopenhagenDanish Dementia Research Centre, Rigshospitalet, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenDanish Dementia Research Centre, Rigshospitalet, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenInstitute of Neurobiology, Heinrich Heine University DüsseldorfInstitute of Physiology, University of ZurichDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenAbstract Background 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 details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Methods Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus. Results We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na+/K+/2Cl− cotransporter NKCC1, the Na+/HCO3 − cotransporter NBCe2, and the Na+/K+-ATPase, but not on the Na+/H+ exchanger NHE1. We demonstrate that pharmacological modulation of CSF secretion directly affects the ICP. Conclusions CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of 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.https://doi.org/10.1186/s12987-022-00358-4Cerebrospinal fluidChoroid plexusOsmosisCotransportIntracranial pressure |
| spellingShingle | Eva K. Oernbo Annette B. Steffensen Pooya Razzaghi Khamesi Trine L. Toft-Bertelsen Dagne Barbuskaite Frederik Vilhardt Niklas J. Gerkau Katerina Tritsaris Anja H. Simonsen Sara D. Lolansen Søren N. Andreassen Steen G. Hasselbalch Thomas Zeuthen Christine R. Rose Vartan Kurtcuoglu Nanna MacAulay Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure Fluids and Barriers of the CNS Cerebrospinal fluid Choroid plexus Osmosis Cotransport Intracranial pressure |
| title | Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure |
| title_full | Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure |
| title_fullStr | Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure |
| title_full_unstemmed | Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure |
| title_short | Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure |
| title_sort | membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure |
| topic | Cerebrospinal fluid Choroid plexus Osmosis Cotransport Intracranial pressure |
| url | https://doi.org/10.1186/s12987-022-00358-4 |
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