Project: Research project

Project Details


The observations by Couper in 1837 are acknowledged as the earliest
description of the toxic syndrome associated with chronic manganese
(Mn) exposure. Since then, many of the neurotoxic aspects of
manganism have been elucidated, yet, there is little known about
Mn transport mechanisms across the blood-brain barrier (BBB), a
crucial step in its accumulation in the CNS. The objective of this
proposal is to identify the transport mechanisms of Mn across this
barrier in the rat, under the general assumption that factor
affecting the rate and extent of Mn transport will affect its
toxicity. The working hypothesis postulates that Mn transport
across the BBB is a carrier-mediated transport system, and that Mn
is transported as a transferrin conjugate, in its trivalent
oxidation state (Mn+3). To test this hypothesis, the "Oldendorf"
single capillary passage method (1971) of in vivo common carotid
artery injection, and the retrograde in situ brain perfusion
technique (Takasato et al., 1984) will be employed. To provide
control over the composition of the incubation media and to
establish uptake, as well as, transendothelial transport kinetics,
bovine brain capillary endothelial cell suspensions (Betz et al.,
1978), and in vitro monolayers of cultured brain capillaries
(Rutten et al., 1987) will be utilized. The cardinal criteria for
a carrier-mediated transport system, such as uptake inhibition,
substrate specificity, counter transport and its metabolic
requirements will be evaluated. Correlation between the temporal
distribution of 54 Mn in specific brain nuclei with the capillary-
transferrin-receptor density, using autoradiography will be
assessed as further support for the role of transferrin in the
transendothelial transport of Mn. The existence of other BBB
transport mechanisms for Mn, in its divalent oxidation state (Mn+2)
will be also evaluated. The possibility that Mn is transported by
a generic "sulfhydryl shuttle", a two step "internalization"
process, or as a lipid soluble compound will be addressed in the
same in vivo and in vitro transport systems.
Effective start/end date7/1/9012/31/95


  • Transportation


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