Disruption of choroid plexus ion transport, barrier integrity, and inflammatory signaling contributes to cerebrospinal fluid (CSF) overproduction and ventriculomegaly in hydrocephalus. Hydrocephalus is a neurological condition characterized by excessive accumulation of CSF within the ventricles, leading to increased ventricular volume and periventricular injury. Surgical intervention, the only current treatment for this disease, works by draining excess CSF from the brain or irreversibly cauterizing the choroid plexus that produces the CSF. It is our hypothesis that pharmaceutical interventions that involved regulation of CSF production would be a less invasive and more scalable option but thus far this approach has not been successful. Our ultimate goal is to identify a treatment that is effective across multiple forms of the disease from pediatric to adult-onset. For this study, we used a congenital hydrocephalus model—the Wistar Polycystic Kidney (WPK) or Transmembrane 67 (Tmem67) rat—which is orthologous to Meckel–Gruber Syndrome type 3 in humans. The Tmem67-/- rat exhibits severe hydrocephalus and demonstrates ciliary dysfunction, and polycystic kidney disease, creating a unique platform for mechanistic and therapeutic investigation. Previously, our laboratory found that SI113, a serum- and glucocorticoid-regulated kinase 1 (SGK1) inhibitor, significantly reduced ventriculomegaly in the Tmem67 rat model of hydrocephalus (Hochstetler et al., 2023). The novelty in the current study is that, instead of solubilizing the compound in dimethyl sulfoxide (DMSO), we used 1-methyl-2-pyrrolidinone (NMP), which may offer a viable alternative since it has been used successfully in clinical studies. Treatment of the animals began on postnatal day 7 (P7) and continued daily until P14. MRI scans were performed before treatment at P7 and after treatment at P15. Wild-type and homozygous animals were divided into several groups: untreated, and those sacrificed 0.5, 2, or 24 hours post-treatment on P15. Results showed that this compound is not only promising in reducing ventriculomegaly, but it was also detectable in the CSF at multiple timepoints. The CSF concentration peaked at the 2-hour timepoint and returned to a level similar to the 0.5 hours timepoint by 24 hours, indicating sustained presence. There was also a measurable compound detected in the plasma for up to 24 hours post-treatment. Together, these findings demonstrate that the compound successfully crosses the blood CSF barrier and blood brain barrier. Western blotting was performed to examine the expression of transient receptor potential vanilloid 4 (TRPV4) and the sodium–potassium–chloride cotransporter 1 (NKCC1), two key transporters in the choroid plexus epithelium that have been implicated in CSF production. The results showed no significant differences in NKCC1 levels, and although TRPV4 was increased at earlier timepoints, it returned to baseline by 24 hours post-treatment. References: Hochstetler AE, et al. (2023) Fluid Barriers CNS 20:61 Funding: Innovator Award from the Hydrocephalus Association and Team Hydro. This abstract was presented at the American Physiology Summit 2026 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.
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