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Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons in the substantia nigra. This neuronal degeneration is associated with a strong microglial activation and iron accumulation in the affected brain structures. The increased iron content may result from an increased iron penetration into the brain parenchyma due to a higher expression of lactoferrin and lactoferrin receptors at the level of the blood vessels and dopaminergic neurons in the substantia nigra in PD. Iron may also accumulate in microglial cells after phagocytosis of dopaminergic neurons. These effects may be reinforced by a lack of up-regulation of the iron storage protein ferritin, as suggested by an absence of change in iron regulatory protein 1 (IRP-1) control of ferritin mRNA translation in PD. Thus, a dysregulation of the labile iron pool may participate in the degenerative process affecting dopaminergic neurons in PD.

Owing to its ability to undergo one-electron reactions, iron transforms the mild oxidant hydrogen peroxide into hydroxyl radical, one of the most reactive species in nature. Deleterious effects of iron accumulation are dramatically evidenced in several neurodegenerative diseases. The work of Youdim and collaborators has been fundamental in describing the accumulation of iron confined to the substantia nigra (SN) in Parkinson’s disease (PD) and to clarify iron toxicity pathways and oxidative damage in dopaminergic neurons. Nevertheless, how the mechanisms involved in normal neuronal iron homeostasis are surpassed, remain largely undetermined. How nigral neurons survive or succumb to iron-induced oxidative stress are relevant questions both to know about the etiology of the disease and to design neuroprotective strategies. In this work, we review the components of neural iron homeostasis and we summarize evidence from recent studies aimed to unravel the molecular basis of iron accumulation and dyshomeostasis in PD.

The consequences of short phases of restricted cerebral blood flow and iron enrichment of striatal tissues resulted in an animal model that could correspond to the basic features of a model for Parkinson’s disease. An automatic and computerized hole-board offers simultaneous data on learning and cognitive memory capabilities, learning of distinct patterns of distributed food pellets found and eaten in a given time, switches between different locations of food in the holes and in different layout patterns. Wistar rats after 60 min of bilateral clamping of the carotid arteries (BCCA) under pentobarbital anesthesia received 1.5 µg FeCl_3 injected one week after BCCA unilaterally into the ventrolateral striatum. The experiments showed that reduced cerebral blood flow and increased iron within the striatal tissue had the effect of retarding reactions. Rats after BCCA and iron need 180 s to find pellets deep inside holes that are distributed in a distinct pattern. During only 60 or 30 s BCCA plus iron rats are no longer able to find the same number of pellets as over 180 s. Rats after BCCA plus NaCl do not show such reduced success. These results point to the idea that cerebral oligemia and increased iron in the striatum stimulate the pathological symptoms of Parkinson’s disease which need also more time to have reaction and success (see Fig. 5). The data covering abbreviated time-spans show how heavily the BCCA + Fe animals are dependent on longer times.

We have quantitated CSF and serum levels of Selenium, iron, copper and zinc by Atomic absorption spectrophotometer in 36 patients with parkinson’s disease all on L-dopa therapy. Out of these 19 showed on or positive response to L-dopa where as 21 patients showed on and off response. These data were compared with 21 healthy controls. The results showed that serum levels of iron, copper and zinc remained unchanged where as in CSF, significant decrease in zinc was found in both on and on/off PD patients indicating the deficiency of zinc which continues in the worsening clinical condition of off patients. The level of copper remained unchanged in both on and on/off PD patients. Iron and selenium increase in CSF of both patients which is a clear evidence of relationship between increased iron and selenium level in brain which could be correlated with decrease in dopamine levels and oxidative stress in PD Patients.

Iron closely regulates the expression of the Alzheimer’s Amyloid Precursor Protein (APP) gene at the level of message translation by a pathway similar to iron control of the translation of the ferritin L- and H mRNAs by Iron-responsive Elements in their 5′untranslated regions (5′UTRs). Using transfection based assays in SH-SY5Y neuroblastoma cells we tested the relative efficiency by which iron, copper and zinc up-regulate IRE activity in the APP 5′UTR. Desferrioxamine (high affinity Fe^3+ chelator), (ii) clioquinol (low affinity Fe/Cu/Zn chelator), (iii) piperazine-1 (oral Fe chelator), (iv) VK-28 (oral Fe chelator), were tested for their relative modulation of APP 5′UTR directed translation of a luciferase reporter gene. Iron chelation based therapeutic strategies for slowing the progression of Alzheimer’s disease (and other neurological disorders that manifest iron imbalance) are discussed with regard to the relative neural toxic action of each chelator in SH-SY5Y cells and in H4 glioblastoma cells.

Evidence to link abnormal metal (iron, copper and zinc) metabolism and handling with Parkinson’s and Alzheimer’s diseases pathology has frequently been reported. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. Metal chelation has the potential to prevent iron-induced oxidative stress and aggregation of alpha-synuclein and beta-amyloid peptides. The efficacy of iron chelators depends on their ability to penetrate the subcellular compartments and cellular membranes where iron dependent free radicals are generated. Thus, natural, non-toxic, brain permeable neuroprotective drugs, are preferentially advocated for “ironing out iron” from those brain areas where it preferentially accumulates in neurodegenerative diseases. This review will discuss the most recent findings from in vivo and in vitro studies concerning the transitional metal (iron and copper) chelating property of green tea and its major polyphenol, (−)-epigallocatechin-3-gallate with respect to their potential for the treatment of neurodegenerative diseases.