Neurotoxicology of dietary iron/manganese interactions

锰是人类和其他哺乳动物的必需营养素，它是参与细胞代谢的许多关键酶的关键辅因子。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表明，膳食缺铁与大脑锰的过度积累有关，特别是在富含多巴胺的大脑区域。迄今为止，锰的积累主要发生在这些脑区的方式和原因仍然未知，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蓄积靶向多巴胺丰富的脑区的机制，并建立与锰神经毒性相关的神经化学变化。该项目的第一个目的是确定多巴胺转运蛋白在锰积累到多巴胺丰富的大脑区域中的作用。提出了体内和体外研究，这些研究将利用饮食和药理学操作来实现这一目标。 该项目的第二个目的是确定由于锰神经毒性和膳食缺铁引起的锰积累导致的多巴胺能区域的神经化学改变。最近的研究表明，锰神经毒性的锥体外系症状是由于异常的γ-氨基丁酸（GABA）代谢，这可能间接改变多巴胺神经生物学引起的PD样行为。GABA代谢紊乱也与缺铁引起的锰积累有关。拟议的体内微透析研究将确定铁状态是否代表锰积累加剧的神经化学改变的风险因素。如果成功，这些研究将为开发旨在预防弱势群体锰积累的药物疗法奠定基础。

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.