BBB Transport of MMT Metabolites

描述（改编自申请人的摘要）：拟议的研究将 提高对锰（Mn）的理解和表征机制 运输到大脑，这是其毒性作用的目标。近期排放 甲基环戊二烯基三羰基锰（MMT）的表征 表明磷酸锰和硫酸锰混合物最适合 机动车尾气中锰的排放特性。 因此，拟议的研究将集中在脑转运动力学， 磷酸锰和硫酸锰，研究结果将与 与氯化锰的传输动力学，模型锰化合物， 以前研究过。一个重要的过程中的毒理学结果的 暴露于金属是它们从血浆进入大脑的运输过程。 毛细血管内皮细胞构成血脑屏障（BBB）。小 关于氯化锰是已知的，实际上没有实验数据存在 关于硫酸锰和磷酸锰跨膜的迁移机制， 血脑屏障是锰在大脑中积累的关键步骤。的目的 因此，建议确定Mn的运输机制（在其 各种形式）跨越这一障碍，根据该协议， Mn穿过BBB的转运程度将最终影响其毒性。的 本提案的具体目标是（1）确定Mn在 在大鼠体外毛细血管细胞培养中，各种化学形式穿过BBB 模型(2)研究Mn通过BBB的体内转运， 微透析技术这些研究的目的是为了表征运输 锰的动力学和识别可能增加的潜在种群 Mn在CNS中沉积的风险，以及由此推断的Mn神经毒性。的 研究将证明锰进入大脑的机制， 体外和体内，并奠定了基础， 用于在锰的条件下操纵转运的治疗方式 中毒这些研究与锰的一些关键问题密切相关 神经毒性还有待研究。(1)比较药代动力学 和毒性的不同锰物种（磷酸盐，硫酸盐和氯化物）， Mn的不同氧化态（2+ vs.3+）。(2)的识别 人群（缺铁）易受锰毒性影响，风险较高。 (3)锰致神经毒性可能机制的探讨 与其在中枢神经系统中的累积相比。

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.