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Cited by 10Cerebrospinal fluid and hydrocephalusIon Transport and Channel RegulationTraumatic Brain Injury and Neurovascular Disturbances

Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models

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Hochstetler, Alexandra, Smith, Hillary, Reed, Makenna, Hulme, Louise, Territo, Paul, Bedwell, Amanda, Persohn, Scott, Perrotti, Nicola +4 more·2023·Fluids and Barriers of the CNS
DOI 10.1186/s12987-023-00461-0PMC PMC10439616
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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.

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Cited by

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Authors
Hochstetler, A., Smith, H., Reed, M., Hulme, L., Territo, P., Bedwell, A., Persohn, S., Perrotti, N., D’Antona, L., Musumeci, F., Schenone, S., & Blazer-Yost, B. L.
Affiliations
  • Indiana University Indianapolis (US)
  • Indiana University School of Medicine (US)
  • Magna Graecia University (IT)
  • University of Genoa (IT)
ORCID
Venue
Fluids and Barriers of the CNS
Publisher
Springer Science and Business Media LLC
Published
2023-08-18
Volume
20
Issue
1
Pages
61-61
ISSN
2045-8118 (ISSN-L)
DOI
10.1186/s12987-023-00461-0
PMC
PMC10439616
OpenAlex
W4385972538
Cited by
10
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 2
FWCI
1.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Fluids and Barriers of the CNS (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
Funders
  • Hydrocephalus Association (Innovator Award, Team Hydro)
  • Mayfield Education and Research Foundation (Research Grant)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
hydrocephalus, SGK1, SGK1 inhibitor, choroid plexus epithelium, cerebrospinal fluid production, ventriculomegaly, drug repurposing
MeSH terms
Brain Injuries, Traumatic, Animals, Biological Transport, Glucocorticoids, Humans, Hydrocephalus, Phosphorylation, Rats

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