Browsing by Author "Jantzie, Lauren"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Characterizing Changes in the Brain During Hydrocephalic Development and Exploring Potential Treatment Strategies
    (2024-05) Reed, Makenna M.; Blazer-Yost, Bonnie; Belecky-Adams, Teri; Cummins, Theodore; Baucum, A. J.; Jantzie, Lauren
    A neurological disorder, hydrocephalus, has an estimated global pediatric prevalence of 380,000 new cases each year [1]. It is a family of diseases that can occur at any age when cerebrospinal fluid builds up within the ventricles of the brain. Thus, the only available treatments are surgical, invasive, and prone to complications. There is a global need for successful treatment strategies without brain surgery. Choroid plexus epithelial cells (CPEC) are responsible for production of cerebrospinal fluid (CSF). Ependymal cells line the ventricles and play roles in CSF maintenance and waste clearance. Astrocytes perform various functions, one being blood-brain barrier (BBB) maintenance. Collectively these cells contribute to brain fluid/electrolyte regulation and barrier integrity. Increased glial fibrillary acidic protein (GFAP) fluorescence, a marker of activated astrocytes, appeared in hydrocephalic (Tmem67-/-) animals by immunohistochemistry as early as postnatal day (P)10. The tight junction proteins expressed in choroid plexus (CP); claudin-1 (Cl-1) and zona occludin 1 (ZO-1) fluorescent intensity increased in P15 hydrocephalic animals compared to wildtype (Tmem67+/+). These cells also contain aquaporins (AQP), aquaporin-1 (AQP1) and aquaporin-4 (AQP4), important in regulating CSF and interstitial fluid (ISF). Increased fluorescent intensity of AQP4 in the subventricular zone and increased AQP1 apical localization and protein amount in the CP was observed in hydrocephalic animals at postnatal day (P)15. Many of these may be targeted for the treatment of hydrocephalus. However, there is no consensus in pathological findings between models of hydrocephalus and these finding may not translate to common pharmacological targets. A transient receptor potential cation channel, subfamily vanilloid, member 4 (TRPV4) antagonist (RN1734) ameliorates hydrocephalus in a rat model of congenital hydrocephalus (Tmem67 model). It was hypothesized that targeting this mechanosensitive ion channel may slow production of CSF by targeting the CP. However, hydrocephalus pathology can have various effects on the brain. Astrocytes were visualized using fluorescent immunohistochemistry of glial fibrillary acidic protein (GFAP) and RN1734 did not seem to change immunoreactivity to wildtype untreated levels. Increased immunoreactivity of TRPV4 and AQP1 was observed in CP of untreated and RN1734 treated Tmem67-/- rats. AQP4 and TRPV4 immunoreactivity increased in the subventricular zone and periventricular white matter (WM) of hydrocephalic rats. With RN1734, TRPV4 immunoreactivity, but not AQP4, had similar immunoreactivity to wildtype untreated. Increased GFAP and AQP immunoreactivity may indicate residual inflammation in the Tmem67-/- rats. More experiments must be done to further elucidate TRPV4’s role in hydrocephalus pathology. Serum and glucocorticoid-regulated kinase 1 (SGK1) is a kinase implicated in cell volume regulation and CSF production. SI113, an SGK1 inhibitor, ameliorates hydrocephalus in the Tmem67 rodent model. The goal of this study was to determine if SI113 could be used with a new solvent other than dimethyl sulfoxide (DMSO), which can have possible toxic effects. 1-methyl-2-pyrrolidinone (NMP) has high solubility and ability to cross the BBB. These studies showed that NMP as a solvent did not have adverse effects on body weight, however thus far, it has not ameliorated hydrocephalus significantly at the concentration used in this study. There is a possibility that the concentration in NMP that we used was not efficacious enough. CSF and blood plasma samples from animals treated with SI113 24 hours and 30 minutes before euthanasia will be used to investigate the concentration of SI113 that remains in the circulation and the amount that crosses the BBB and blood-cerebrospinal fluid (BCSFB) barriers. We hope that the results will inform dosage for our future studies. Future studies may also examine SI113 mechanism of action in hydrocephalus. This thesis addresses hydrocephalus cell and molecular pathology in the Tmem67 model and examines potential treatment strategies. Future directions include comparing models of hydrocephalus to find common treatment strategies in the hope to find pharmaceutical strategies to better manage human hydrocephalus.
  • Thumbnail Image
    Item
    The Effects of Hydrocephalus on the Retina and the Optic Nerve
    (2023-12) Loftin, Michelle; Belecky-Adams, Teri; Blazer-Yost, Bonnie; Jantzie, Lauren
    Papilledema is the swelling of the optic disc resulting from increased cranial pressure (ICP). A diagnosis of papilledema is important to not only treat pathologies of the eye, but it also can be an important indicator of underlying brain pathology since the subarachnoid space surrounding the optic nerve is contiguous with the brain. Therefore, the increased cranial pressure from brain pathology can be transmitted to the eye. Thus, it is important to have further understanding of the mechanism of papilledema and the anatomical and cellular changes that occur with sustained ICP. To study papilledema, a reproducible post hemorrhagic hydrocephalic (PHH) rat model was used to study the changes of the retina, optic disc, and optic nerve when exposed to high levels of ICP. Multiple retinal changes were noted in the PHH rats including decreased retinal thickness in the peripheral retina in female rats and increased retinal thickness close to the optic disc in male rats. PHH caused a decrease in ganglion cell layer thickness in the peripheral retina. In addition, vascular changes were noted with the PHH rats having an increased occurrence of enlarged retinal vasculature. In addition, the PHH rats had an increased optic disc width from analyzed retinal sections and increased optic disc diameter on optical coherence tomography (OCT). Also, PHH caused a decrease in retinal ganglion cells (RGC). These experiments confirm that PHH model in rats can produce retinal and optic disc phenotypes that are similar to those found in human pathology. Therefore, future studies are indicated utilizing the PHH rat model to provide further understanding of the mechanism of papilledema progression and to allow for the study of possible therapeutics.