Research On The Relationship Between Iron Metablism In The Central Nervous System And Parkinson's Disease

Iron accumulation in the substantia nigra (SN) has been demonstrated in Parkinson's disease (PD). Irreversible and regional specific neurodegeneration and the presence of Lewy bodies are the essential pathological hallmarks of PD. The ultimate cause of death of dopamine (DA) neurons in PD is not clear, but a growing body of evidence indicates that increased oxidative stress is one of the main culprits. By its enhancing effect on the generation of oxidative stress in cells, iron might play a key role in the development of PD. Little knowledge is available on how the brain senses and signals that it requires iron or how iron can be removed from the brain. The newly discovered iron transporters, such as divalent metal transporter 1 (DMT1), Ferroportin 1 (FP1), offer a new opportunity for us to understand the accumulation of iron in the PD patients brain. DMT1, identified as the first mammalian transmembrane iron transporter in 1997, is responsible for iron uptake from small intestine and transport from endosomes to cytoplasm. The mRNA of DMT1 has two forms, DMT1+IRE and DMT1-IRE form. The DMT1+IRE form transcript contains a canonical iron-responsive element (IRE) in the 3' untranslated region, whereas that of DMT 1-IRE form lacks the IRE motif. FP1 is a transmembrane iron transporter that responses for iron efflux from the cell. In 2000, the gene encoding this protein was identified by three groups separately at the same time. However, the exact role of these newly identified iron transport proteins in the brain iron metabolism has not yet been identified. Based on our previous study, using immunohistochemistry and high performance liquid chromatography electrochemical detection (HPLC-ECD), we determine the relationship of elevated iron content and DA cell loss in the SN in l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) treated mice. We also use immunohistochemistry, immunofluorescence and RT-PCR to determine the changed expression of DMT 1 and FP1 in MPTP treated mice and 6-hydroxydopamine (6-OHDA)lesioned rats. Expression patterns of DMT 1 and FPI in the normal mouse and rat brain are also studied. The results were as follows:1. 3 days after MPTP treatment, the iron staining in the mice SN increased significantly (P<0.05), 7 days later, it showed a further increase. While in the striatum (Str), no change was found in iron staining after 3 days of MPTP treatment, however, 7 days after MPTP treatment, it showed apparent increase (P<0.05).2. Two isoforms of DMT1 expressed in the brain of mice. They were,distributed mostly in the cortex, hippocampus, striatum, medial habenular nucleus, thalamus, SN, arcuate nucleus and ependymal cells around the third ventricle. In the CA1 and CA3 region of hippocampus, the expression of DMT 1-IRE was lower than that of DMT1+IRE, while in the medial habenular nucleus and ependymal cells around the third ventricle, the expression of DMT 1 -IRE was much higher than that of DMT1+IRE.3. The number of tyrosine hydroxylase (TH) immunoreactive neurons in the mice SN decreased 65.87% and 68.16% in the group of MPTP 3d and MPTP 7d, respectively. The DA content in the Str also decreased about 29.83% and 54.20%, respectively.4. In MPTP treated mice, the expression of DMT1+IRE in the SN showed no significant increase after 3 days of MPTP treatment, while 7 days later, it showed a significant increase. While in the Str, its expression increased after 3 days of MPTP treatment, a further increase was found after 7 days of MPTP treatment.5. In MPTP treated mice, the expression of DMT 1 -IRE in the SN increased in both two groups, as well as its changed expression in the Str.Abstract6. The expression of DMT 1-IRE in the arcuate nucleus of the mice increased after MPTP treatment (P<0.05).7. The expression of DMT1 -IRE in CA1 and CAS region of hippocampus of the mice increased after 3 days of MPTP treatment, however, after 7 days of MPTP treatment, its expression decreased a little.8. There was no change in the expression of transferrin receptor (TfR) in the SN...