INFUSION OF IRON INTO THE RAT SUBSTANTIA-NIGRA - NIGRAL PATHOLOGY ANDDOSE-DEPENDENT LOSS OF STRIATAL DOPAMINERGIC MARKERS

Iron has recently been suggested to contribute to the pathogenesis of Parkinson's disease (PD) because of the finding of increased iron leve ls in the substantia nigra pars compacta (SNc) above those of control patients. Iron is capable of catalyzing numerous reactions which could lead to free radical formation and oxidative damage to DNA, proteins, lipid membranes, and other biological molecules. Neurodegeneration in the SNc of the PD brain may be a consequence of increased iron, which promotes these cytotoxic reactions. To test whether excess iron could play a causative role in the degeneration of nigral neurons, we infus ed 1.25-6.3 nmol of iron into the rat substantia nigra (SN) unilateral ly utilizing two different infusion protocols. All infusates were isos motic and pH-balanced in a citrate-bicarbonate vehicle. Animals were d ecapitated at either 1 or 2 months postinfusion. Striatal tissue was a ssayed for biogenic amines by HPLC and the remaining brainstem was pro cessed for histological analysis. Iron-stained coronal sections reveal ed 1) no left/right staining difference with vehicle infusion, 2) a do se-dependent iron accumulation in the infused SN that was restricted t o the zona compacta and dorsal-most zona reticularis when the lowest i ron concentration was infused, and 3) a dose-dependent reduction in SN volume. Thionine-stained sections revealed neuronal loss and accompan ying reactive gliosis within an area that corresponded closely to that of increased iron staining. These degenerative changes were more exte nsive in animals infused via a side-by side vs. a sequential protocol. Neurochemically, there was a highly significant correlation between t he amount of iron infused intranigrally and magnitude of reductions in striatal DA, DOPAC, and HVA within the ipsilateral striatum. These da ta indicate that iron infusion into the SN can cause degenerative chan ges within the SN and that these changes can be restricted to the SNc region when low amounts of iron are infused. The data further support the hypothesis that iron-induced degeneration may contribute to the pa thogenesis of PD.