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Transfer mechanisms for low molecular weight lipid insoluble molecules into the developing brain


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Ek, Carl Joakim 2001 , 'Transfer mechanisms for low molecular weight lipid insoluble molecules into the developing brain', PhD thesis, University of Tasmania.

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The internal environment of the central nervous system (CNS) is protected from its
surrounding milieu by barriers, which selectively facilitate and restrict the entry of
molecules in and out of the CNS. These barriers form early during development,
however, their selectivity in the developing brain appears to be different from those that
protect the adult brain. The reasons for the differences in the CNS barriers between
young and adult animals are still unclear. The experiments in this thesis were performed
in order to obtain morphological and physiological explanations for the changes in the
transfer of lipid insoluble molecules into the CNS that occur during development.
Quantitative studies with radioactive markers in parallel with experiments using a tracer
that could be visualised were conducted in an attempt to correlate physiological uptake
with the structural studies. A marsupial species, the grey short-tailed South-American
opossum (Monodelphis domestica), was used in all experiments since it is born at an
early stage of brain development, and thus is a more accessible model than any
eutherian animal during a similar developmental period. The transfer of lipid insoluble
molecules has previously not been studied at such early stages of brain development.
All experiments were carried out in accordance with NHMRC guidelines and with the
approval of the University of Tasmania Ethics Committee. Lipid insoluble radioactive
markers were injected into opossum pups and blood, cerebrospinal fluid (CSF) and
brain samples were collected to assess initial rate of uptake and steady-state CSF/plasma and brain/plasma ratios. These experiments showed that the steady-state
ratios for small lipid insoluble molecules were high in early development compared to
the adult and that they decreased during development due to a reduction in CNS barrier
permeability with age. Possible routes by which lipid insoluble molecules enter the
brain were investigated using a 3000 molecular weight biotin-dextran and visualising it
under the light and electron microscope. This tracer allowed localisation of a small inert
lipid insoluble molecule at the blood-CNS interfaces. Quantitative measurements of
CSF uptake showed that the dextran penetrates across the brain barriers to an extent
similar to other small lipid insoluble molecules and thus validates the dextran as a
suitable tracer. Under the electron microscope, it appeared that cells of the blood-CSF
interface at birth already exhibited tight-junctions, which are the fundamental structures
of the brain barriers. These junctions seemed to impede the intercellular movement of
the biotin-dextran. Uptake into cells at the blood-CSF interface and lack of extracellular biotin-dextran in the brain suggest that in the immature brain the route of penetration
from blood to brain may be predominantly via the CSF rather than directly across the
cerebral vessels of the developing brain.

Item Type: Thesis - PhD
Authors/Creators:Ek, Carl Joakim
Keywords: Brain chemistry, Neurochemistry, Molecular neurobiology, Lipids
Copyright Holders: The Author
Copyright Information:

Copyright 2001 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

Thesis (Ph.D.)--University of Tasmania, 2002. Includes bibliographical references

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