College of Chemistry and Chemical Engineering , Central South University , Changsha 410083 , P. R. China.
Institute of Surface Analysis and Chemical Biology , University of Jinan , Jinan 250022 , P. R. China.
ACS Chem Neurosci. 2019 Jun 19;10(6):2777-2785. doi: 10.1021/acschemneuro.9b00009. Epub 2019 May 13.
The aberrant autoxidation of norepinephrine (NE) in the presence of oxygen, which is accelerated by Fe(III), has been linked to the pathogenesis of the Parkinson's disease (PD). Adenosine triphosphate (ATP), as a neurotransmitter whose release can be stimulated by tissue damage and oxidative stress, is co-stored and often co-released with NE in presynaptic terminals. We have shown previously that ATP inhibits the iron-catalyzed dopamine oxidation, thereby decreasing the production of certain neurotoxins such as 6-hydroxydopamine. Whether ATP plays a similar role in Fe(III)-catalyzed NE oxidation and how it maintains the NE stability have not been investigated. Here, we studied the coordination in a ternary complex among NE, Fe(III), and ATP, and found that Fe(III) is coordinated as a octahedral center by NE and ATP. Voltammetry and mass spectrometry were employed to examine this ternary complex's modulation of the NE autoxidation. NE-Fe(III)-ATP plays a protective role to modulate the autoxidation and Fe(III)-catalyzed oxidation of NE. The ternary complex can be detected in the substantia nigra (SN), locus coeruleus (LC), and striatum regions of C57BL/6 wild-type mice. In contrast, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse brains displayed a significant decrease of the ternary complex in the SN region and an increase in the LC and striatum areas. We posit that the ternary complex is produced by noradrenergic neurons as a protective regulator against neuronal damage and oxidative stress, contributing to the lower vulnerability of LC neurons with respect to that of SN neurons.
去甲肾上腺素（NE）在氧存在下的异常自氧化，在铁（III）存在下加速，与帕金森病（PD）的发病机制有关。三磷酸腺苷（ATP）作为一种神经递质，其释放可以被组织损伤和氧化应激刺激，与 NE 一起在突触前末端共同储存和共同释放。我们之前已经表明，ATP 抑制铁催化的多巴胺氧化，从而减少某些神经毒素的产生，如 6-羟多巴胺。ATP 是否在铁（III）催化的 NE 氧化中发挥类似作用，以及它如何维持 NE 的稳定性尚未得到研究。在这里，我们研究了 NE、Fe(III)和 ATP 之间三元复合物的配位，并发现 Fe(III)被 NE 和 ATP 配位为八面体中心。伏安法和质谱法被用来研究这种三元复合物对 NE 自氧化的调节作用。NE-Fe(III)-ATP 发挥保护作用，调节 NE 的自氧化和 Fe(III)催化的氧化。该三元复合物可在 C57BL/6 野生型小鼠的黑质（SN）、蓝斑核（LC）和纹状体区域检测到。相比之下，1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠脑 SN 区的三元复合物显著减少，LC 和纹状体区的三元复合物增加。我们假设三元复合物是由去甲肾上腺素能神经元产生的，作为一种保护调节剂，以防止神经元损伤和氧化应激，从而降低 LC 神经元相对于 SN 神经元的易损性。
