Steeling for a Possible Iron-Parkinson Connection

Courtesy of Kurt Jellinger IF IT ONLY WERE ELEMENTARY: Element distribution found by energy dispersive x-ray analysis in neuromelanin from nigral neuron in a PD patient. Adv Neurol, 60:267-71, 1993. Patients with Parkinson disease endure a progressive loss of neurons, especially dopaminergic, in the substantia nigra and other subcortical nuclei. Hallmarks of PD also include intracytoplasmic Lewy bodies and abnormal neurites, especially in the subcortical nuclei and hippocampus of affected patients. Recent research shows that iron is associated with several of these hallmarks, as the evidence links PD with free radicals generated from iron accumulation in the midbrain. Lewy bodies, for example, include redox-active iron in patients with PD, and postmortem analyses reveal elevated iron levels in the substantia nigra. Iron, however, is a cofactor for tyrosine hydroxylase, the enzyme responsible for dopamine synthesis. The precise mechanism through which iron could lead to PD's symptoms is not fully characterized; researchers need to determine if it is a primary phenomenon or a secondary issue, notes Jack Sipe, adjunct professor and senior consultant in neurology at the Scripps Research Institute in La Jolla, Calif.1 "However, there are tantalizing clues that iron accumulation in specific brain areas, such as the substantia nigra in PD or hippocampus in Alzheimer's, may play a role in promoting neurodegeneration through the formation of highly destructive oxygen free radicals," he says. To complicate matters further, elevated iron is only one factor that seems to influence cell redox state and, therefore, disease progression. For instance, the substantia nigra of patients with PD expresses low levels of glutathione, one of the most important defenses against free radicals. Yet, levels of monoamine oxidase B, involved in dopamine metabolism, show an age-related increase. Such factors could contribute to PD, says Julie Andersen, associate professor, Buck Institute for Age Research in Novato, Calif. PD might not be a single disease, though; it could represent a syndrome initiated by several factors, many of which remain poorly characterized. A recent cDNA microarray gene-expression analysis of the current benchmark PD model, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity, identified a "large number" of previous unknown events in the biochemical cascade that culminates in neuronal cell death. The authors noted that the "profound complexity" of this "domino effect" helps explain why a single drug has yet to be identified for neuroprotection in affected patients.2 "It is quite possible that PD might have other primary factors that would allow different targeted treatments with the dopamine-deficit as the final common pathway," adds Kurt Jellinger, director of the Institute of Clinical Neurobiology in Vienna.3 IRON TREATMENT Iron chelation might offer one logical approach to treatment. In one study,4 Andersen and her coworkers assessed the ability of transgenic expression of ferritin (an endogenous protein that binds iron) or oral administration of the chelator clioquinol, to attenuate MPTP toxicity. In animals, both approaches were well-tolerated and protected against the toxin, bolstering suggestions that chelation might be an effective strategy. Previous studies using R-apomoranphine and other chelators showed that they have several biochemical and pharmacological effects other than just on iron level. "Ferritin is selective for iron and therefore provides more definitive proof of the role of iron in toxin-induced Parkinsonism," Andersen notes. "Although our studies strongly suggest that iron is involved as a causative agent in the MPTP model of Parkinson's disease, it would be of interest to run similar studies in other models. The data also suggest that iron chelation is a feasible therapy,... but of course clinical trials need to be run." Other researchers are more cautious about chelation's therapeutic potential, especially given the lack of a specific and sensitive test for early, presymptomatic PD. Scripps' Sipe notes that between 50% and 80% of the dopaminergic neurons in the substantia nigra are destroyed or degenerate before PD's clinical symptoms emerge. "Thus, chelation may be too little, too late for PD sufferers," he says. Moreover, Jellinger comments that preliminary data, currently in press, indicate that neuronal cell death precedes the iron elevation in the MPTP model. Although contrary evidence exists, he remarks that these new data might suggest that iron accumulation is not the primary lesion. Future research, says Jellinger, must help investigators to understand iron's role in PD, including better characterization of iron transport in the brain. Other studies should include those on iron toxicity, oxidative stress, the role of the Fenton reaction, and disorders of the electron transport chain. Mark Greener (markgreener1@aol.com) is a freelance writer in Cambridgeshire, UK References 1. J.C. Sipe et al., "Brain iron metabolism and neurodegenerative disorders," Dev Neurosci, 24:188-96, 2002. 2. M.B. Youdim et al., "Early and late molecular events in neurodegeneration and neuroprotection in Parkinson's disease MPTP model as assessed by cDNA microarray; the role of iron," Neurotox Res, 4:679-89, 2000. 3. K.A. Jellinger, "Recent developments in the pathology of Parkinson's disease," J Neural Transm, 62(suppl):347-76, 2002. 4. D. Kaur et al., "Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo. A novel therapy for Parkinson's disease," Neuron, 37:899-909, March 27, 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

Steeling for a Possible Iron-Parkinson Connection

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