Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models
Abstract Background Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Fluids and Barriers of the CNS |
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| Online Access: | https://doi.org/10.1186/s12987-023-00461-0 |
| _version_ | 1797451766112976896 |
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| author | Alexandra Hochstetler Hillary Smith Makenna Reed Louise Hulme Paul Territo Amanda Bedwell Scott Persohn Nicola Perrotti Lucia D’Antona Francesca Musumeci Silvia Schenone Bonnie L. Blazer-Yost |
| author_facet | Alexandra Hochstetler Hillary Smith Makenna Reed Louise Hulme Paul Territo Amanda Bedwell Scott Persohn Nicola Perrotti Lucia D’Antona Francesca Musumeci Silvia Schenone Bonnie L. Blazer-Yost |
| author_sort | Alexandra Hochstetler |
| collection | DOAJ |
| description | Abstract Background Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the excess CSF. Importantly, there are no long-term, effective pharmaceutical treatments and this represents a clinically unmet need. Many forms of hydrocephalus involve dysregulation in water and electrolyte homeostasis, making this an attractive, druggable target. Methods In vitro, a combination of electrophysiological and fluid flux assays was used to elucidate secretory transepithelial electrolyte and fluid flux in a human cell culture model of the choroid plexus epithelium and to determine the involvement of serum-, glucocorticoid-induced kinase 1 (SGK1). In vivo, MRI studies were performed in a genetic rat model of hydrocephalus to determine effects of inhibition of SGK1 with a novel inhibitor, SI113. Results In the cultured cell line, SI113 reduced secretory transepithelial electrolyte and fluid flux. In vivo, SI113 blocks the development of hydrocephalus with no effect on ventricular size of wild-type animals and no overt toxic effects. Mechanistically, the development of hydrocephalus in the rat model involves an increase in activated, phosphorylated SGK1 with no change in the total amount of SGK1. SI113 inhibits phosphorylation with no changes in total SGK1 levels in the choroid plexus epithelium. Conclusion These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus. |
| first_indexed | 2024-03-09T14:59:08Z |
| format | Article |
| id | doaj.art-8074d949e52d428b89b2452191283773 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-03-09T14:59:08Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-8074d949e52d428b89b24521912837732023-11-26T14:00:47ZengBMCFluids and Barriers of the CNS2045-81182023-08-0120111410.1186/s12987-023-00461-0Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical modelsAlexandra Hochstetler0Hillary Smith1Makenna Reed2Louise Hulme3Paul Territo4Amanda Bedwell5Scott Persohn6Nicola Perrotti7Lucia D’Antona8Francesca Musumeci9Silvia Schenone10Bonnie L. Blazer-Yost11Department of Biology, SL358, Indiana University Purdue University IndianapolisDepartment of Biology, SL358, Indiana University Purdue University IndianapolisDepartment of Biology, SL358, Indiana University Purdue University IndianapolisDepartment of Biology, SL358, Indiana University Purdue University IndianapolisDepartment of Medicine, Indiana University School of MedicineDepartment of Medicine, Indiana University School of MedicineDepartment of Medicine, Indiana University School of MedicineDipartimento di Scienze della Salute, Università” Magna Graecia” di CatanzaroDipartimento di Scienze della Salute, Università” Magna Graecia” di CatanzaroDepartment of Pharmacy, University of GenoaDepartment of Pharmacy, University of GenoaDepartment of Biology, SL358, Indiana University Purdue University IndianapolisAbstract Background Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the excess CSF. Importantly, there are no long-term, effective pharmaceutical treatments and this represents a clinically unmet need. Many forms of hydrocephalus involve dysregulation in water and electrolyte homeostasis, making this an attractive, druggable target. Methods In vitro, a combination of electrophysiological and fluid flux assays was used to elucidate secretory transepithelial electrolyte and fluid flux in a human cell culture model of the choroid plexus epithelium and to determine the involvement of serum-, glucocorticoid-induced kinase 1 (SGK1). In vivo, MRI studies were performed in a genetic rat model of hydrocephalus to determine effects of inhibition of SGK1 with a novel inhibitor, SI113. Results In the cultured cell line, SI113 reduced secretory transepithelial electrolyte and fluid flux. In vivo, SI113 blocks the development of hydrocephalus with no effect on ventricular size of wild-type animals and no overt toxic effects. Mechanistically, the development of hydrocephalus in the rat model involves an increase in activated, phosphorylated SGK1 with no change in the total amount of SGK1. SI113 inhibits phosphorylation with no changes in total SGK1 levels in the choroid plexus epithelium. Conclusion These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.https://doi.org/10.1186/s12987-023-00461-0HydrocephalusChoroid plexusTransepithelial epithelial ion transportSerum- and glucocorticoid-induced kinase 1 |
| spellingShingle | Alexandra Hochstetler Hillary Smith Makenna Reed Louise Hulme Paul Territo Amanda Bedwell Scott Persohn Nicola Perrotti Lucia D’Antona Francesca Musumeci Silvia Schenone Bonnie L. Blazer-Yost Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models Fluids and Barriers of the CNS Hydrocephalus Choroid plexus Transepithelial epithelial ion transport Serum- and glucocorticoid-induced kinase 1 |
| title | Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models |
| title_full | Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models |
| title_fullStr | Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models |
| title_full_unstemmed | Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models |
| title_short | Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models |
| title_sort | inhibition of serum and glucocorticoid induced kinase 1 ameliorates hydrocephalus in preclinical models |
| topic | Hydrocephalus Choroid plexus Transepithelial epithelial ion transport Serum- and glucocorticoid-induced kinase 1 |
| url | https://doi.org/10.1186/s12987-023-00461-0 |
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