Preclinical Studies using a Serum Glucocorticoid Induced Kinase (SGK1) Inhibitor for the Treatment of Hydrocephalus

Hydrocephalus, a serious clinical condition caused by accumulation of cerebrospinal fluid (CSF), has no treatment other than invasive and repetitive surgeries. Serum and glucocorticoid-regulated kinase-1 (SGK1) is a serine/threonine protein kinase that belongs to the AGC (protein kinase A, G, and C) family of kinases. Our laboratory has found that an SGK1 inhibitor, SI113, reduced ventriculomegaly in the Tmem67 rat model of hydrocephalus (Hochstetler et al., 2023). In the published study, dimethyl sulfoxide (DMSO) was used to solubilize the SI113 compound for injection, however, DMSO is not a clinically usable solvent. We hypothesize that replacing DMSO with 1-Methyl-2-pyrrolidinone (NMP) could offer a viable alternative, as it has been used successfully in clinical studies. To test this, we conducted an in vivo study, administering SI113 dissolved in NMP to the Tmem67 rat model of congenital hydrocephalus. T2 MRI was performed to compare the extent of ventriculomegaly between treated and untreated groups in both Tmem67−/− (hydrocephalic) and Tmem67+/+ (wild-type) rats. Results showed the ventriculomegaly was reduced in the treated group with no effect on body weight. We also collected CSF and blood plasma samples from animals treated with SI113 24 hours and 30 minutes before euthanasia. We used these samples to investigate the concentration of SI113 remaining in the circulation and the amount that crosses the blood brain barrier (BBB) and blood CSF barrier (BCSFB). Our data show that the drug concentration in plasma at 24 hours is significantly lower compared to 30 minutes. Additionally, the concentration in CSF is higher at 30 minutes compared to 24 hours. To refine our understanding, we are also analyzing samples collected at the 2-hour mark to compare all groups and determine the optimal dosage for our future studies. qRT-PCR was used to investigate potential downstream cellular pathways influenced by SGK1 inhibition at 0.5, 2 and 24 hours post treatment. We identified effects on two key genes which have been previously implicated in CSF production, Sodium-Potassium-Chloride Cotransporter 1(NKCC1)and STE20/SPS1-related, proline alanine-rich kinase (SPAK). The results indicate a significant decrease in the expression levels of both genes in choroid plexus in the hydrocephalic animals treated 2 hours. This suggests that SI113 treatment impacts these pathways and that the timing of treatment may play a critical role in modulating gene expression. Future studies may also examine SI113 mechanism of action in hydrocephalus. SGK1 has yet to be investigated in the choroid plexus and may provide another target for pharmacological treatment. References: Hochstetler AE, et al. (2023) Fluid Barriers CNS 20:61. This research was conducted with the support of DoD congressional Directed Medical Research Program Grants #HT94252310296 and #HT94252310401 (BBY). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.