Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models.
Choroid plexus
Hydrocephalus
Serum- and glucocorticoid-induced kinase 1
Transepithelial epithelial ion transport
Journal
Fluids and barriers of the CNS
ISSN: 2045-8118
Titre abrégé: Fluids Barriers CNS
Pays: England
ID NLM: 101553157
Informations de publication
Date de publication:
18 Aug 2023
18 Aug 2023
Historique:
received:
22
11
2022
accepted:
28
07
2023
medline:
21
8
2023
pubmed:
19
8
2023
entrez:
18
8
2023
Statut:
epublish
Résumé
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. 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. 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. These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.
Identifiants
pubmed: 37596666
doi: 10.1186/s12987-023-00461-0
pii: 10.1186/s12987-023-00461-0
pmc: PMC10439616
doi:
Substances chimiques
Glucocorticoids
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
61Subventions
Organisme : Hydrocephalus Association
ID : Innovator Award, Team Hydro
Organisme : Mayfield Education and Research Foundation
ID : Research Grant
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
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