Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease

Increasing evidence has confirmed that nigral iron accumulation and activation of NMDAreceptors (NRs) contribute to the neurodegeneration ofdopamine (DA)neurons in Parkinson'sdisease (PD).Earlierworkindicated that activation ofNRsparticipated inironmetabolism inthe hippocampus.However, the relationshipbetween activation of NRsandiron accumulationinDAneuronsof thesubstantia nigra inPDwasunknown.Inthis study,our results showed that NRs inhibitors MK-801 and AP5 protected nigrostriatal projection system and reduced nigral iron levels of 6-hydroxydopamine (6-OHDA)-induced PD rats. In vitro studies demonstrated that NMDA treatment increased the expression of iron importer divalent metal transporter 1 (DMT1) and decreased the expression of iron exporter ferropotin 1 (Fpn1), whichwere dependent on iron regulatory protein 1 (IRP1). This led to increased intracellular iron levels and intensified thedecrease inmitochondrial transmembrane potential inMES23.5dopaminergicneurons. Inaddition, we reported that MK801 and neuronal nitric oxide synthase inhibitor could antagonize 6-OHDA-induced upregulation of IRP1 andDMT1 and down-regulation of Fpn1, thus attenuating 6-OHDA-induced iron accumulation in MES23.5 cells. This suggested that 6-OHDA-induced activation of NRsmight modulate the expression of DMT1 and Fpn1 via the neuronal nitric oxide synthase-IRP1 pathway.