BBB Transport of MMT Metabolites

Project: Research project

Project Details

Description

DESCRIPTION(adapted from applicant's abstract): The proposed research will
;improve the understanding and characterize the mechanism(s) of manganese (Mn)
transport into the brain, a target for its toxic effects. Recent emission
characterizations of methylcyclopentadienyl manganese tricarbonyl (MMT)
indicate that a mixture of manganese phosphate and manganese sulfate best fit
the emissions characteristics of Mn from the tail pipe of vehicles.
Accordingly, the proposed studies will focus on brain transport kinetics of
manganese phosphate and manganese sulfate, and the findings will be correlated
with the transport kinetics of manganese chloride, a model Mn compound that has
been previously studied. An important process in the toxicologic outcome of
exposure to metals is their transport from plasma into the brain across the
capillary endothelial cells that comprise the blood-brain barrier (BBB). Little
is known about manganese chloride, and virtually no experimental data exist
regarding the transport mechanisms of manganese sulfate and phosphate across
the BBB, a crucial step in Mn accumulation in the brain. The objective of this
proposal is, therefore, to identify the transport mechanism(s) of Mn (in its
various forms) across this barrier, under the assumption-that the rate and
extent of Mn transport across the BBB will ultimately affect its toxicity. The
specific aims of this proposal are to (1) Determine the transport of Mn in
various chemical forms across the BBB in a rat in vitro capillary cell culture
model. (2) Study the in vivo transport of Mn across the BBB with the in situ,
microdialysis technique. These studies are aimed at characterizing transport
kinetics of Mn and identifying potential populations that may be at increased
risk for Mn deposition in the CNS, and by inference, Mn neurotoxicity. The
studies will demonstrate the mechanism(s) by which Mn enters the brain both in
vitro and in vivo, and lays the foundation for mechanistically based
therapeutic modalities for manipulating transport in conditions of Mn
intoxication. The studies closely relate to a number of critical issues in Mn
neurotoxicity that have yet to be studied. (1) The comparative pharmacokinetics
and toxicity of different Mn species (phosphate, sulfate, and chloride) and
different oxidative states of Mn (2+ vs. 3+). (2) The identification of
populations (Fe-deficient) susceptible and at heightened risk to Mn toxicity.
(3) Delineation of the potential mechanisms of Mn-induced neurotoxicity
vis-a-vis its accumulation in the CNS.
StatusFinished
Effective start/end date5/1/014/30/02

Funding

  • National Institute of Environmental Health Sciences: $210,105.00

ASJC

  • Cell Biology

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