Browsing by Subject "Central nervous system"

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    Metabolism and CNS Distribution of Selected Histone Deacetylase Inhibitors
    (2024-03) Zhang, Wenqiu
    Brain tumors are the leading cause of cancer-related death in children and efficacious treatment remains a critical unmet need. The blood-brain barrier (BBB) is a major hurdle for effective delivery of treatments for tumors in the central nervous system (CNS). While the paracellular transport of large, hydrophilic molecules is largely limited by tight junctions, efflux transporter systems are a key element of the BBB that can limit the penetration of lipophilic drugs. Histone deacetylase inhibitors (HDACIs) have been widely explored for their application in oncology, including the field of neuro-oncology. Despite their high in vitro potency and CNS-penetration-favorable physicochemical properties, the in vivo efficacy of HDACIs has been poor for CNS tumor treatment. This lack of in vitro-in vivo correlation may be in part attributed to poor CNS distribution. In this thesis project, we investigated the CNS distribution of three potent HDACIs, panobinostat, vorinostat, and quisinostat, following systemic administration. We characterized the systemic pharmacokinetics and CNS distributional kinetics of these compounds in wild-type and transgenic mice lacking p-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp), two major efflux transporters expressed at the BBB. The in vitro stability studies show that all three hydroxamic acid-based HDACIs are enzymatically metabolized in mouse plasma, highlighting the need for careful sample handling to have accurate measurements of in vivo drug concentrations. In vivo experiments in the different mouse genotypes show that the CNS distribution of panobinostat and quisinostat is moderately limited by P-gp, but not Bcrp. Although the CNS penetration of vorinostat was not restricted by P-gp and Bcrp, its small unbound CNS tissue-to-plasma partition coefficients suggest that other efflux transporters could be involved. In addition, our results show that a tolerable dosing regimen of panobinostat would not result in adequate CNS exposure of unbound panobinostat in patients. In summary, our data show that the lack of adequate exposure of the active moieties can be a major reason for the lack of efficacy of these HDACIs in the CNS when systemically delivered. This result indicates that alternative approaches to improve delivery (e.g., convection-enhanced delivery or focused ultrasound) should be considered.
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    Orexin and NPY interactions in feeding behavior.
    (2009-11) Ferri, Erwin D.
    Obesity results from an imbalance between energy intake and energy expenditure. The central nervous system (CNS) has a complex interconnected circuitry that regulates feeding behavior. The hypothalamus is the principal region in the central nervous system regulating energy intake and energy expenditure. Important advances have been made identifying hypothalamic neuronal networks, neuropeptide transmitters and the discovery of circulating peptides that send signals to the brain regarding the body’s nutritional status. However, the full set of neuronal pathways that initiate changes in ingestive behavior or energy expenditure remain undefined. This dissertation examines the roles of two specific neuropeptides, orexin A (OXA) and neuropeptide Y (NPY) in food regulation. Several lines of evidence suggest that orexin and NPY interact in modulating feeding behavior and these dissertation studies further substantiate this premise. Previous research conducted in this laboratory showed that subthreshold doses of OXA and NPY agonists stimulate feeding when administered simultaneously. The current set of studies shows effects of individual and simultaneous central administration of subthreshold doses of NPY and OXA antagonists on feeding. The first study established dose-response parameters for both OXA and NPY antagonists. The OXA antagonist was injected into the lateral hypothalamic area (LHa) whereas the NPY antagonist was injected into the hypothalamic paraventricular nucleus (PVN). The objective was to ascertain sub-threshold doses for both of these neuropeptides antagonists within these brain sites. The study showed that the subthreshold dose for both the NPY and the orexin antagonist was 100 pmol. The second study was the central administration of both subthreshold doses of the NPY antagonist and the orexin antagonist simultaneously, within the PVN and LHA respectively. Individual administration of subthreshold doses of the orexin and NPY antagonists in the LHA and PVN respectively caused no inhibition of food intake, whereas simultaneous administration of subthreshold doses of the orexin and NPY antagonists significantly inhibited food intake. Significant differences (p < 0.001) were obtained at all time points (0-1 h, 0-2 h, 0-4 h and 0-24 h) comparatively with vehicle. The experiments conducted further substantiate the premise of a functional relationship between OXA and NPY that involves corresponding pathways between the LHA and the PVN.