Neurotoxicology of dietary iron/manganese interactions

锰是人类和其他哺乳动物必需的营养物质，它是参与细胞代谢的许多关键酶的关键辅助因子。然而，已知极高的脑锰浓度会导致神经毒性，症状类似于帕金森病（PD）。最近的啮齿动物研究将饮食铁缺乏与过量的脑锰积累联系起来，特别是在富含多巴胺的大脑区域。迄今为止，锰积累主要发生在这些大脑区域的方式和原因尚不清楚，尽管有人假设多巴胺转运蛋白可能介导了这一过程。该项目的目的是明确锰积累针对富含多巴胺的大脑区域的机制，并建立与锰神经毒性相关的神经化学变化。该项目的第一个目标是确定多巴胺转运体在锰积聚到富含多巴胺的大脑区域中的作用。提出了体内和体外研究，将利用饮食和药理操作来实现这一目标。

Manganese is an essential nutrient for humans and other mammals, and it functions as a critical cofactor for many key enzymes involved in cellular metabolism. However, exceedingly high brain manganese concentrations are known to cause neurotoxicity with symptoms similar to Parkinson's disease (PD). Recent rodent studies have linked dietary iron deficiency with excessive brain manganese accumulation, specifically in dopamine-rich brain regions. To date, it is still unknown how and why manganese accumulation occurs primarily in these brain regions, although it has been hypothesized that the dopamine transporter may mediate this process. The objective of this project is to specifically determine the mechanism by which manganese accumulation targets dopamine-rich brain regions and establish neurochemical changes associated with manganese neurotoxicity. The first aim of the project is to ascertain the role of the dopamine transporter in the accumulation of manganese into dopamine-rich brain regions. Both in vivo and in vitro studies are proposed which will utilize dietary and pharmacological manipulations to accomplish this aim. The second aim of the project is to identify neurochemical alterations in dopaminergic regions due to both manganese neurotoxicity and manganese accumulation caused by dietary iron deficiency. Recent studies suggest that the extrapyramidal symptoms of manganese neurotoxicity are due to abnormal gamma-aminobutryic acid (GABA) metabolism which may indirectly alter dopamine neurobiology causing PD-like behaviors. Disturbances in GABA metabolism have also been linked to manganese accumulation due to iron deficiency. Proposed in vivo microdialysis studies will determine whether iron status represents a risk factor for neurochemical alterations that are exacerbated by manganese accumulation. If successful, these studies will lay the foundation for the development of a pharmacological therapy aimed at the prevention of manganese-accumulation in vulnerable populations.