Thesis (Ph.D.)--University of Adelaide, Dept. of Anatomical Sciences, 2002? / Bibliography: leaves 318-367.

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Bipolar disorder (BD), previously known as manic depressive disorder, is associated with recurring episodes of depression and mania/hypomania. Currently, no definitive biological mechanisms have been pinpointed with regards to the origin and progression of BD, however, inflammation and oxidative stress have been shown to present in the brains of individuals with BD. Notably, other neurodegenerative disorders which also contain an inflammatory component including Alzheimer’s disease and Multiple Sclerosis display with disruption of the brain blood barrier (BBB). We thus propose a model of BD wherein BBB disruption facilitates inflammation and oxidative stress induced neural damage. This study looked to utilize amphetamine (AMPH) induced mania model and lipopolysaccharide (LPS) induced inflammatory model to represent BD like conditions in rats and to assess BBB permeability. We observed elevated locomotor data in response to AMPH administration and a trend of increased BBB permeability across regions following low dose chronic AMPH injections. In the LPS induced BBB permeability model, we did not detect any elevated serum C-reactive protein (CRP) or tumour necrosis factor alpha (TNF-α) levels but did see significantly elevated BBB permeability in the LPS group and lithium pre-treatment providing some protection against BBB permeability in one of our cohorts. These trends were further corroborated by a follow-up study and thus warrant further investigation into the mechanistic nature of BBB breakdown in this model. This may provide a breakthrough in understanding the pathophysiology of BD and the underlying mechanistic effects of lithium, paving the way for new more target therapeutic remedies to combat this debilitating disorder. / Thesis / Master of Science (MSc)

The blood-brain barrier (BBB) is composed of brain microvascular endothelial cells (BMECs), pericytes, and astrocytic endfeet, which regulate the transport of molecules into and out of the brain. BMECs possess intrinsic barrier properties that limit the passage of approximately 98% of small molecules into the brain in healthy individuals. However, in some brain diseases, the BBB undergoes structural and functional alterations, which can contribute to disease progression. In this study, we aimed to investigate the BBB by exploring the effects of endothelial cell stretching and the optimal dimensionality of stretching to enhance endothelium barrier tightness in Chapter 2. Subsequently, we developed an endothelium gradient stretching device to further examine the stretching effect in Chapter 3. Additionally, we investigated the promotion of endothelium tightness through the use of electrospun fibers, wherein we controlled the pore size. Based on these findings, we designed and fabricated an organ chip model that incorporates mechanical stretching, microfluidic techniques, electrospun fibers, and hydrogel extracellular matrix (ECM). The results of permeability testing demonstrated that this chip significantly improved the tightness of microvascular selective transport ability and has the potential to be used in drug sorting for central nervous system (CNS) diseases.

Bibliography: leaves 318-367. Examines the blood-brain barrier in normal and pathological conditions induced by intravascular and extravascular insults. Intravascular insults were induced by administration of Clostridium perfringens prototoxin; extravascular insults were induced by an impact acceleration model for closed head injury to induce traumatic brain injury. Also examines the integrity of the blood-brain barrier ultrastructurally and by its ability to exclude endogenous and exogenous tracers. Also studies the expression of 2 blood-brain barrier specific proteins, endothelial barrier antigen (EBA) and glucose transporter 1 (GLUT1)

Bibliography: leaves 318-367. / x, 367 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the blood-brain barrier in normal and pathological conditions induced by intravascular and extravascular insults. Intravascular insults were induced by administration of Clostridium perfringens prototoxin; extravascular insults were induced by an impact acceleration model for closed head injury to induce traumatic brain injury. Also examines the integrity of the blood-brain barrier ultrastructurally and by its ability to exclude endogenous and exogenous tracers. Also studies the expression of 2 blood-brain barrier specific proteins, endothelial barrier antigen (EBA) and glucose transporter 1 (GLUT1) / Thesis (Ph.D.)--University of Adelaide, Dept. of Anatomical Sciences, 2002?

Bibliography: leaves 318-367. / x, 367 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the blood-brain barrier in normal and pathological conditions induced by intravascular and extravascular insults. Intravascular insults were induced by administration of Clostridium perfringens prototoxin; extravascular insults were induced by an impact acceleration model for closed head injury to induce traumatic brain injury. Also examines the integrity of the blood-brain barrier ultrastructurally and by its ability to exclude endogenous and exogenous tracers. Also studies the expression of 2 blood-brain barrier specific proteins, endothelial barrier antigen (EBA) and glucose transporter 1 (GLUT1) / Thesis (Ph.D.)--University of Adelaide, Dept. of Anatomical Sciences, 2002?

No description available.

L'efficacité thérapeutique de la majorité des molécules développées pour traiter les pathologies du système nerveux central (SNC) n’est pas optimale en raison des caractéristiques anatomiques et physiologiques uniques de la barrière hémato-encéphalique (BHE) qui joue un rôle majeur dans la protection du parenchyme nerveux. Une stratégie permettant de délivrer des agents pharmacologiques dans le cerveau est de détourner un système physiologique : la transcytose régulée par des récepteurs (RMT). Cette stratégie implique la conjugaison d’agents pharmacologiques à des vecteurs développés pour cibler spécifiquement des récepteurs présents au niveau de la BHE et impliqués dans des processus de RMT. Nous avons eu pour objectif de développer de nouveaux vecteurs spécifiques de récepteurs exprimés au niveau de la BHE. Nous avons tout d’abord construit une banque de phages présentant les vecteurs afin de réaliser différentes stratégies de sélection par phage display. A l’issue d’étapes de criblage, les vecteurs sélectionnés ont été produits et caractérisés (affinités pour les récepteurs, compétitions avec les ligands naturels…). Nous avons ensuite évalué le potentiel des vecteurs les plus prometteurs à transporter une biomolécule. Pour ce faire, deux vecteurs par récepteur ont été fusionnés à la région Fc d’une IgG1 humaine et la capacité des conjugués à traverser un modèle de BHE in vitro a été évaluée. Enfin, nous avons évalué la distribution cérébrale des vecteurs, chez la souris in vivo. L’ensemble de nos résultats démontre l'intérêt du ciblage des récepteurs choisis et le potentiel des de nos vecteurs pour des applications de délivrance cérébrale. / The vast majority of the molecules developed to treat neurological diseases do not reach their targets efficiently enough because of the unique anatomical and physiological features of the blood-brain barrier (BBB) which plays a major protective role. Hijacking a physiological system named receptor-mediated transcytosis (RMT) is considered a promising route for brain delivery of pharmacological. This strategy involves the conjugation of pharmacological agents to vector molecules developed to specifically target receptors present at the BBB and involved in RMT processes. We aimed to develop new vectors specific for receptors expressed at the BBB. First, we constructed a phage library presenting vectors in order to perform various phage display selection strategies. Following screening steps, the selected vectors were produced and characterized (affinities for the receptors, competitions with natural ligands…). Then, we assessed the potential of the most promising vectors to carry a biomolecule. Two vectors per receptor were fused to a human IgG1 Fc region and the fusion proteins were tested for their ability to cross an in vitro model of the BBB. Finally, we evaluated the brain distribution of the vectors, in mice in vivo. Our results demonstrate the potential of our receptor-targeting vectors for brain drug delivery.