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.
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