Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats
Abstract Background Cerebrospinal fluid (CSF) is produced and absorbed at a balanced rate to maintain a constant intracranial pressure (ICP). The CSF dynamics are, however, disturbed in several pathological conditions, leading to elevated ICP, which may have fatal outcomes if left untreated. Treatme...
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BMC
2025-04-01
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| Series: | Fluids and Barriers of the CNS |
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| Online Access: | https://doi.org/10.1186/s12987-025-00652-x |
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| author | Mette N. Jensen Ida M. E. Israelsen Jonathan H. Wardman Dennis B. Jensen Daniel B. Andersen Trine L. Toft-Bertelsen Martin F. Rath Jens Juul Holst Mette M. Rosenkilde Nanna MacAulay |
| author_facet | Mette N. Jensen Ida M. E. Israelsen Jonathan H. Wardman Dennis B. Jensen Daniel B. Andersen Trine L. Toft-Bertelsen Martin F. Rath Jens Juul Holst Mette M. Rosenkilde Nanna MacAulay |
| author_sort | Mette N. Jensen |
| collection | DOAJ |
| description | Abstract Background Cerebrospinal fluid (CSF) is produced and absorbed at a balanced rate to maintain a constant intracranial pressure (ICP). The CSF dynamics are, however, disturbed in several pathological conditions, leading to elevated ICP, which may have fatal outcomes if left untreated. Treatment options for these conditions are limited to invasive neurosurgery, and novel pharmacological approaches to manage ICP in pathology are sought. Here, we aimed to demonstrate the potential of the glucagon-like peptide-1 receptor (GLP-1R) as such a target. Methods We administered male rats with intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) GLP-1R agonist (exendin-4) or antagonist (exendin-9-39) followed by in vivo determination of CSF dynamics. GLP-1R expression in the CSF-secreting choroid plexus was demonstrated with RNAScope in situ hybridization and western blotting and transporter activity with radio-isotope flux assays. Results GLP-1R activation increased the CSF secretion rate with an associated elevation of the ICP, whereas inhibition of the receptor reduced the rate of CSF secretion. These effects were observed with central, but not peripheral, administration of the agonist and antagonist, suggesting receptor expression on the luminal, CSF-facing side of the choroid plexus, which aligned with GLP-1R-mediated modulation of luminally-expressed transporters in excised choroid plexus. Low level GLP-1R expression was demonstrated in the choroid plexus at mRNA and protein levels. Conclusion Modulation of GLP-1R affects CSF production, which suggests that GLP-1R-mediated signalling may have the potential to control ICP in pathological conditions with disturbed CSF homeostasis. |
| format | Article |
| id | doaj-art-1947d2b72cfd46fda4c0ee2bb1aa4a20 |
| institution | DOAJ |
| issn | 2045-8118 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj-art-1947d2b72cfd46fda4c0ee2bb1aa4a202025-08-20T03:15:09ZengBMCFluids and Barriers of the CNS2045-81182025-04-0122111310.1186/s12987-025-00652-xGlucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in ratsMette N. Jensen0Ida M. E. Israelsen1Jonathan H. Wardman2Dennis B. Jensen3Daniel B. Andersen4Trine L. Toft-Bertelsen5Martin F. Rath6Jens Juul Holst7Mette M. Rosenkilde8Nanna MacAulay9Department 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 Biomedical Sciences, 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 Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Neuroscience, Faculty of Health and Medical Sciences, University of CopenhagenAbstract Background Cerebrospinal fluid (CSF) is produced and absorbed at a balanced rate to maintain a constant intracranial pressure (ICP). The CSF dynamics are, however, disturbed in several pathological conditions, leading to elevated ICP, which may have fatal outcomes if left untreated. Treatment options for these conditions are limited to invasive neurosurgery, and novel pharmacological approaches to manage ICP in pathology are sought. Here, we aimed to demonstrate the potential of the glucagon-like peptide-1 receptor (GLP-1R) as such a target. Methods We administered male rats with intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) GLP-1R agonist (exendin-4) or antagonist (exendin-9-39) followed by in vivo determination of CSF dynamics. GLP-1R expression in the CSF-secreting choroid plexus was demonstrated with RNAScope in situ hybridization and western blotting and transporter activity with radio-isotope flux assays. Results GLP-1R activation increased the CSF secretion rate with an associated elevation of the ICP, whereas inhibition of the receptor reduced the rate of CSF secretion. These effects were observed with central, but not peripheral, administration of the agonist and antagonist, suggesting receptor expression on the luminal, CSF-facing side of the choroid plexus, which aligned with GLP-1R-mediated modulation of luminally-expressed transporters in excised choroid plexus. Low level GLP-1R expression was demonstrated in the choroid plexus at mRNA and protein levels. Conclusion Modulation of GLP-1R affects CSF production, which suggests that GLP-1R-mediated signalling may have the potential to control ICP in pathological conditions with disturbed CSF homeostasis.https://doi.org/10.1186/s12987-025-00652-xGLP-1ICPCSFChoroid plexusHydrocephalusIIH |
| spellingShingle | Mette N. Jensen Ida M. E. Israelsen Jonathan H. Wardman Dennis B. Jensen Daniel B. Andersen Trine L. Toft-Bertelsen Martin F. Rath Jens Juul Holst Mette M. Rosenkilde Nanna MacAulay Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats Fluids and Barriers of the CNS GLP-1 ICP CSF Choroid plexus Hydrocephalus IIH |
| title | Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats |
| title_full | Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats |
| title_fullStr | Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats |
| title_full_unstemmed | Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats |
| title_short | Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats |
| title_sort | glucagon like peptide 1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats |
| topic | GLP-1 ICP CSF Choroid plexus Hydrocephalus IIH |
| url | https://doi.org/10.1186/s12987-025-00652-x |
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