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

Autor: Hochstetler A; Department of Biology, SL358, Indiana University Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN, 46202, USA., Smith H; Department of Biology, SL358, Indiana University Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN, 46202, USA., Reed M; Department of Biology, SL358, Indiana University Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN, 46202, USA., Hulme L; Department of Biology, SL358, Indiana University Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN, 46202, USA., Territo P; Department of Medicine, Indiana University School of Medicine, Indianapolis, USA., Bedwell A; Department of Medicine, Indiana University School of Medicine, Indianapolis, USA., Persohn S; Department of Medicine, Indiana University School of Medicine, Indianapolis, USA., Perrotti N; Dipartimento di Scienze della Salute, Università' Magna Graecia' di Catanzaro, Catanzaro, Italy., D'Antona L; Dipartimento di Scienze della Salute, Università' Magna Graecia' di Catanzaro, Catanzaro, Italy., Musumeci F; Department of Pharmacy, University of Genoa, Genoa, Italy., Schenone S; Department of Pharmacy, University of Genoa, Genoa, Italy., Blazer-Yost BL; Department of Biology, SL358, Indiana University Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN, 46202, USA. bblazer@iu.edu.
Jazyk: angličtina
Zdroj: Fluids and barriers of the CNS [Fluids Barriers CNS] 2023 Aug 18; Vol. 20 (1), pp. 61. Date of Electronic Publication: 2023 Aug 18.
DOI: 10.1186/s12987-023-00461-0
Abstrakt: 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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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