96,150,151 In PD, there is progressive accumulation of intracellular iron in SNc neurons and microglia.152-154 Why this occurs is uncertain,153,155 but the excess nigral iron is likely to enhance local oxidative stress. Ordinarily, accumulation of GSK1349572 tissue iron is accompanied by concomitant increases in local ferritin levels, which serve to moderate the risk of local redox toxicity that would Inhibitors,research,lifescience,medical otherwise be associated with the increased iron. However, in PD, the expected increase in local ferritin does not occur.155,156 Iron is chemically inactive when bound to ferritin as Fe3+, whereas unbound iron in the ferrous state (Fe2+) can combine with H2O2 in the Fenton reaction

to produce the reactive hydroxyl radical (OH·).152 This and other reactive oxygen species (ROS) are also generated in the course of DA metabolism and turnover.148 Activities of TH and monoamine oxidase generate H2O2. In the presence of ferrous iron, the superoxide anion and H2O2 – two weakly reactive free radical species – can Inhibitors,research,lifescience,medical combine in the Haber- Weiss reaction to produce the more reactive OH· radical; this is believed to be the dominant, pathway for biological production of the OH· radical.155 Neuromelanin (NM) may play a

role in nigral, and possibly LC, degeneration, but whether that role is toxic or protective Inhibitors,research,lifescience,medical remains uncertain. In humans and nonhuman Inhibitors,research,lifescience,medical primates, both the DA-producing neurons of SNc and the NA-producing neurons of LC are darkly pigmented due to perikaryal accumulation of NM within double-membrancd organelles known as NM granules.152,157 NM. is produced by spontaneous autooxidation of cytosolic DA and NA in SNc and LC neurons, respectively.152 The selective

vulnerability of SNc Inhibitors,research,lifescience,medical and LC neurons in both PD and MPTP-induced parkinsonism prompted early suggestions that NM might contribute to the neurodegenerative process. Recent studies suggest NM may have the opposite effect, at least, early in the disease. For example, it was noted that the nigral DA neurons most susceptible to early loss in PD – those in the ventral tier of the SNc – typically contain lower amounts of NM than do their less vulnerable counterparts in the dorsal tier.16 Biochemical studies have shown that as NM is synthesized and accumulates intracellularly during the life of an SNc neuron, it appears to be capable of binding and inactivating Sclareol redox-active metal ions (in particular Fe2+), intrinsically generated quinones and ROS,152,158 and environmental toxins such as paraquat.157 While SNc iron levels are still relatively low early in the course of PD, NM contains a preponderance of highaffinity iron -binding sites that, could oxidize redox-active Fe2+ and chelate the inactive Fe3+ that results, thereby reducing the potential for oxidative stress.