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Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models
Alexandra Hochstetler1, Hillary Smith1, Makenna Reed1
1Department of Biology, SL358, Indiana University Purdue University Indianapolis, 723 West Michigan Street, Indianapolis, IN, 46202, USA.
Insights
A novel inhibitor, SI113, targeting serum-, glucocorticoid-induced kinase 1 (SGK1), effectively blocks hydrocephalus development in a preclinical model. This discovery offers a promising pharmaceutical approach for treating hydrocephalus, addressing a significant unmet medical need.
Area of Science:
- Neuroscience
- Pharmacology
- Physiology
Background:
- Hydrocephalus is characterized by pathological cerebrospinal fluid (CSF) accumulation and ventriculomegaly.
- Current treatments rely on surgical CSF drainage, with no effective long-term pharmaceutical options available.
- Dysregulation of water and electrolyte homeostasis in hydrocephalus presents a druggable target.
Purpose of the Study:
- To investigate the role of serum-, glucocorticoid-induced kinase 1 (SGK1) in hydrocephalus.
- To evaluate the efficacy of a novel SGK1 inhibitor, SI113, in preclinical models of hydrocephalus.
Main Methods:
- In vitro electrophysiological and fluid flux assays in human choroid plexus epithelial cells.
- In vivo MRI studies in a genetic rat model of hydrocephalus.
- Assessment of SGK1 phosphorylation and total levels.
Main Results:
- SI113 reduced secretory transepithelial electrolyte and fluid flux in vitro.
- SI113 prevented hydrocephalus development in vivo without affecting wild-type animals or causing toxicity.
- Hydrocephalus development correlated with increased phosphorylated SGK1; SI113 inhibited this phosphorylation.
Conclusions:
- These findings establish a strong preclinical foundation for SGK1 inhibitors as a potential pharmaceutical treatment for hydrocephalus.
- Targeting SGK1 represents a promising therapeutic strategy for hydrocephalus.
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.
