BBB Transport of MMT Metabolites

描述(改编自申请者的摘要)：建议的研究将 提高对锰(Mn)机理的认识和表征(S) 输送到大脑中，这是其毒性作用的目标。新近排放 甲基环戊二烯基三甲基锰(MMT)的表征 表明磷酸锰和硫酸锰的混合物最适合 汽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，这些发现将是相关的 利用氯化锰的传输动力学，一种模型锰化合物具有 已经被研究过了。在毒理学结果中的一个重要过程 暴露在金属中是它们从血浆进入大脑的过程 毛细血管内皮细胞构成血脑屏障(BBB)。一点儿 已知的是氯化锰，而且几乎没有实验数据存在 关于硫酸锰和磷酸盐的跨膜转运机制 血脑屏障，这是大脑中锰积累的关键步骤。这样做的目的是 因此，建议确定Mn在ITS中的传输机制(S 各种形式)跨越这一障碍，在假设下-利率和 跨血脑屏障的锰转运程度将最终影响其毒性。这个 这项建议的具体目标是(1)确定锰在土壤中的传输 大鼠体外毛细血管细胞培养中血脑屏障的不同化学形态 模特。(2)原位研究锰在血脑屏障中的转运。 微透析技术。这些研究的目的是描述运输的特征 锰的动力学和识别可能增加的潜在种群 中枢神经系统中锰沉积的风险，由此推断，锰的神经毒性。这个 研究将展示锰进入大脑的机制(S)，在两种情况下 体外和体内，并为以机械为基础的 锰条件下操控转运的治疗方法 喝醉了。这些研究与MN的一些关键问题密切相关 神经毒性尚待研究。(1)比较药代动力学 以及不同形态的锰(磷酸盐、硫酸盐和氯化物)和 不同的锰的氧化状态(2比3)。(2)身份识别 (缺铁的)人群对锰中毒敏感且风险较高。 (3)锰致神经毒性的可能机制 相对于它在中枢神经系统的积累。

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.