ironing out parkinson's disease: is therapeutic treatment with iron chelators a real...

Aging Cell

(2002)

1

, pp17–21

© Anatomical Society of Great Britain and Ireland 2002

17

Blackwell Science, Ltd

REVIEW

Iron chelation: a therapy for Parkinson’s disease?, D. Kaur and J. K. Andersen

Ironing out Parkinson’s disease: is therapeutic treatment with iron chelators a real possibility?

Deepinder Kaur and Julie K. Andersen

Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945, USA

Summary

Levels of iron are increased in the brains of Parkinson’sdisease (PD) patients compared to age-matched controls.This has been postulated to contribute to progressionof the disease via several mechanisms including exacer-bation of oxidative stress, initiation of inflammatoryresponses and triggering of Lewy body formation. Inthis minireview, we examine the putative role of iron inPD and its pharmacological chelation as a prospectivetherapeutic for the disease.Key words: ferritin; iron chelators; iron; oxidative stress;Parkinson’s disease; therapy.

Introduction

Parkinson’s disease is a slow but progressive disorder. Its cardinalclinical features include resting tremor, rigidity, difficulty ininitiating movement and postural instability. It occurs as a con-sequence of degeneration of dopamine-producing neurones ofa region of the midbrain called the substantia nigra (SN). Underhealthy conditions these neurones release dopamine into thestriatum, a region in the ventral forebrain, thereby helping tocontrol the nerves and muscles involved in movement andco-ordination. Severe depletion of dopamine in the striatumresulting from nigral dopaminergic cell death is the primarybiochemical defect in Parkinson’s disease (PD). It is still obscureas to what triggers SN cell death but there are strong indicationsthat it is mediated by oxidative stress.

A major role for iron in the pathogenesis of PD (reviewed inBerg

et al

., 2001) has been suggested by several pieces of evi-dence, namely: (a) levels of iron are increased in PD brains com-pared to healthy controls, (b) the region of iron accumulationco-localizes with the region of degeneration, i.e. the SN, (c) ironcan enhance the production of free radicals resulting in oxidative

stress, the most likely cause of dopaminergic cell death in thePD SN and (d) iron has been demonstrated to interact withthe protein alpha-synuclein, resulting in its aggregation andsuggesting a role for iron in Lewy body formation, a major path-ological hallmark of PD. Further credence is given to the roleof iron in PD by the protection afforded by iron chelators invarious paradigms of the disease. This minireview revisits thepostulates behind iron’s hypothesized role in the disease andexplores the use of iron chelators as a possible therapy.

The iron paradox

Iron has been selected by nature to play an essential role in anenormous array of dynamic biological processes owing to itsunique physicochemical properties. Depending on the environ-ment, it is capable of not only varying its oxidation state butalso its electron spin and redox potential. It thus offers enormouscapacity to serve multiple roles in complex biological reactionsvia its ability to exist in more than one state. On the other hand,if not appropriately shielded, ferrous iron can participate in one-electron transfer reactions (e.g. Fenton reaction, Haber–Weissreaction) leading to the production of extremely toxic freeradicals (reviewed in Comporti, 2002). Intracellular iron levelsare therefore stringently regulated to keep limited amountsof iron in what is called a ‘labile iron pool’ (LIP) which providesenough iron to keep vital iron-dependent reactions going butlimits the availability of iron to participate in free radical-generating chemistry. A good example of this ‘iron paradox’operates in the dopaminergic neurones of the SN, the samepopulation of cells lost in PD. On the one hand, iron is requiredas a co-factor by the enzyme tyrosine hydroxylase for thesynthesis of dopamine. On the other, it promotes the oxidationof dopamine, releasing H

2

O

2

in the process. H

2

O

2

thus releasedundergoes oxidation via the Fenton reaction in the presence offerrous iron giving rise to highly reactive and toxic hydroxylradicals. Iron also catalyses the conversion of excess dopamineto neuromelanin, an insoluble black–brown pigment thataccumulates in all dopaminergic neurones in humans with age.Neuromelanin in general is neuroprotective and sequesters redoxactive ions with a high affinity for Fe

3+

. However, when boundto excess Fe

3+

, neuromelanin tends to become a pro-oxidantreducing Fe

3+

back to Fe

2+

, which is then released from theneuromelanin due to weak affinity. This increases the fractionof iron capable of reacting with H

2

O

2

. Dopaminergic neuronesthus need to regulate levels of iron very stringently to keephydroxyl radicals under check without compromising dopaminesynthesis.

Correspondence

Julie K. Andersen, PhD, Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945, USA. Tel.: +1 415 209 2070; fax: +1 415 209 2231; e-mail: [email protected]

Accepted for publication

18 June 2002

ACE_001.fm 7 Wednesday, August 14, 2002 4:28 PM



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Iron elevation in PD – primary or secondary?

Total SN iron levels measured by various methods have beenreported to be elevated in PD patients vs. age-matched controls.This increase has been found to be confined to the substantianigra pars compacta, the area of PD-related cell loss in the SN.There is no direct evidence as to whether iron accumulation isa primary cause of PD or occurs as secondary event consequentto neuronal injury. Increases in the levels of iron in the SN inanimal models of the disease, including in 6-hydroxydopamine(6-OHDA) lesioned rats (He

et al

., 1996) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated monkeys (Mochizuki

et al

., 1994), suggest that iron accumulation occurs as a con-sequence of toxin-induced neuronal degeneration. However,a primary role for iron has been suggested by the efficacy ofdirect brain infusions of ferric chloride in producing disease-likealterations including significant decreases in striatal dopamineand dopamine-related behavioural abnormalities (Ben-Shachar& Youdim, 1991). In addition, an iron-loaded mouse modeldeveloped via feeding a high iron diet to weanling animals overa 1-month period was found to result in marked depletion ofSN glutathione levels, an event considered to be one of theearliest detectable biochemical lesions in PD and to render theanimals more susceptible to MPTP (Lan & Jiang, 1997a).

A number of recent publications have demonstrated thatgenetic mutations in proteins involved in iron metabolism resultin various types of neurodegeneration including parkinsonian-like pathologies. An insertional mutation occurring in humansin the ferritin light polypeptide gene, for example, results in adominant adult-onset basal ganglia disease with extrapyramidalfeatures similar to PD (Curtis

et al

., 2001). Histochemical analysisrevealed aggregates of ferritin and iron in brains from thesepatients. It was suggested that incorporation of a mutant lightchain into ferritin partially compromises the structure and functionof the molecule, leading to release of iron, causing oxidative stressand subsequent cell death. Another recent report on mice deficientin iron regulatory protein 2 (IRP2) demonstrating misregulatediron metabolism and neurodegenerative disease also suggestsa primary role for iron in neurodegeneration and movementdisorder (La Vaute

et al

., 2001). These reports suggest that ironmay play a direct role in neurodegeneration associated with PD.

Iron and endogenous neurotoxin generation

Researchers have hypothesized that under conditions of chronicoxidative stress, a diversion of dopamine metabolism towardsaberrant oxidative routes may be induced. A new mechanismfor dopamine toxicity related to iron accumulation in PD hasbeen recently proposed based on this concept. Pezzella

et al.

(1997) have reported that products of lipid peroxidation, whichare elevated in the Parkinsonian brain, can in the presence of anabnormal accumulation of iron convert dopamine to 6-OHDA. Thisagent, in turn, is able to elicit selective destruction of peripheralcatecholinergic nerve endings via spontaneous oxidative conver-sion to potentially toxic dopaminergic quinone species. Oxidation

of dopamine in the presence of ferrous ions demonstrated thatnovel modifications of dopamine side-chains occurred, resultingin formation of potentially toxic metabolites. It was suggestedthat these reaction pathways become functionally important onlyafter primary toxic processes are underway, perhaps amplifyingthose degenerative events that eventually lead to dopaminergiccell death (Napolitano

et al

., 1999). These findings stress thepossible contribution of iron to the generation of endogenousneurotoxins and thence to the pathogenesis of PD.

Iron and alpha-synuclein aggregation

Lewy bodies are intracytoplasmic inclusions that occur indegenerating neurones in the Parkinsonian brain. Both alpha-synuclein and ubiquitin are found in the aggregates which formthese Lewy bodies. Mutations in the gene for alpha-synucleinhave been associated with familial cases of PD, suggesting thatalterations in alpha-synuclein protein may be involved in thepathogenesis of the disease. Hashimoto

et al

. (1999) recentlyperformed a series of

in vitro

experiments demonstrating thatiron-induced oxidative stress can result in aggregation of alpha-synuclein. Further experiments by Osterova-Golts

et al

. (2000)carried out in neuroblastoma cells over-expressing either wildtype or mutant forms of alpha-synuclein demonstrated that ironin combination with other free radical generators stimulatesintracellular aggregates containing both alpha-synuclein andubiquitin. In another study, by Munch

et al

. (2000), advancedglycation end-products (AGEs), markers of iron-induced oxidativestress, were found to promote cross linking of alpha-synucleinin the brains of incidental Lewy body disease patients, generallyviewed as being pre-Parkinsonian. Recently, Golts

et al

. (2002)demonstrated the presence of iron-induced alterations in thefluorescence of the four-tyrosine residues found in the alpha-synuclein protein, suggestive of metal-related conformationalchanges which could eventually lead to protein aggregation.These studies link iron to a major pathological hallmark of PDand reinforce a more critical role for iron in disease pathogenesis.

Iron and NF-kappa B activation

NF-kappa B is a redox-sensitive transcription factor which trans-activates numerous genes involved in inflammatory responsessuch as cytotoxic cytokines (e.g. TNF-alpha, IL-1 and IL-6). NF-kappa B has been found to be activated in the microglia of theSN pars compacta of PD patients along with increased levels ofits target cytokines. Recent studies demonstrate a pivotal rolefor iron in activation of NF-kappa B which is preventable by ironchelators (Youdim

et al

., 1999). Thus iron-mediated oxidativestress and cytokine elevation may act in concert to induce pro-gressive neurodegeneration in PD.

Ferritin, the natural cellular iron chelator

Ferritin is the major iron storage molecule in the body, keepingiron in a non-reactive form within cells. It is composed of

ACE_001.fm Page 18 Wednesday, August 14, 2002 4:28 PM



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24 subunits consisting of both heavy (H) and light (L) subunitswhich perform complementary functions. While the H subunithas a ferroxidase activity which acts to convert reactive ferrousion to stable ferric ion, the L subunit facilitates the long-termstorage of ferric iron. Each ferritin complex can sequester upto 4500 atoms of iron as ferrihydrite. Several studies supportthe notion that ferritin acts as a protectant against oxygenradical-mediated damage. Presence of an oxidant-responseelement in the promotor of both ferritin genes suggests thatup-regulation of ferritin under stress is one of the protectivemechanisms which cells employ to counter iron-mediatedoxidative stress. Our own unpublished data from transgenicmouse lines expressing elevated H-chain ferritin levels in the SNdemonstrate that these animals display significant resistanceagainst MPTP-induced toxicity via reduction of toxin-associatedoxidative stress.

Whether excess iron observed in the PD brain is ‘free’ orbound to ferritin is not clear. Different research groups havereported increased, decreased or unaltered levels of this proteinin association with the disease. Studies by Griffiths

et al

. (1999)suggest that ferritin in diseased brain is heavily loaded with iron.This implies that even if there is a compensatory increase inferritin levels which can initially act to counter excess iron accu-mulation, eventually ferritin molecules become saturated withiron and cannot chelate additional iron molecules. It should benoted that release of iron from ferritin does not occur as a partof normal physiological processes but may occur under patho-logical conditions or on exposure to redox cycling xenobiotics.Nitric oxide and H

2

O

2

, which are present in abundance in theSN, both negatively effect the synthesis of ferritin and may alsocause iron release from ferritin. Drugs such as nitric oxidesynthase inhibitors or other antioxidants may therefore be usefulin promoting adequate ferritin function as an endogenous ironchelator

Pharmacological iron chelation as a therapy for PD

Because iron is part of numerous biological processes, aberrantiron accumulation in PD can likely contribute to progression ofthe disease in several ways. This implies that if iron accumulationis countered, it can check the progression of the disease by morethan one mechanism. Chelation of iron as a therapeutic alternat-ive for PD has interested many investigators. However, cautionmust be exercised in choosing the right kind of iron chelatorsince reactivity of iron varies greatly depending on the environ-ment that the chelator provides (reviewed by Welch

et al

.,2002). It is preferable to select a chelator which stabilizes ferrousiron thereby preventing iron from participating in redox reac-tions. A ferric-stabilizing chelator could also be protective if itprevents ferric iron from binding to neuromelanin and becom-ing recycled into ferrous iron. Some chelators bind both ferricand ferrous forms but, owing to the greater stability of the ferricchelate, tend to oxidize ferrous to ferric iron generating freeradicals in the process. A similar problem is associated with iron

chelators which cause the release of ferritin-bound iron. Besidesthese inherent inadequacies, the number of possible ironchelators for therapeutic use in PD is limited by the difficultyposed by intake across the blood–brain barrier and by the riskof systemic toxicity.

Desferrioxamine was one of the earliest iron chelatorsemployed in animal studies of PD to assess the role of iron inthe disease (Tanaka

et al

., 1991). It is a powerful chelating agentwhich displaces iron from neuromelanin. When administered incombination with alpha-tocopherol, it was found to inhibit ironaccumulation and oxidative stress and to increase dopamineconcentrations to normal values in the MPTP animal model(Lan & Jiang, 1997b). Besides iron chelation, desferrioxaminehas also been suggested to have antioxidant properties and acapacity to activate mitochondrial complex I (Glinka

et al

., 1998)which is seen to be systemically inhibited in PD patients. Theefficacy of this drug is, however, limited by its high cerebral andocular toxicity and its inability to cross the blood–brain barrier.

R-apomorphine (R-APO), a dopamine D1–D2 receptor agon-ist, is considered a powerful anti-Parkinson’s drug. It is also avery potent iron chelator and free radical scavenger and wasreported to afford protection against MPTP-induced neuro-toxicity in mice based on these properties (Grunblatt

et al

., 1999).The neuroprotective properties of APO were attributed by theauthors to its iron chelating and radical scavenging propertiesrather than its actions as a dopamine receptor agonist, sinceits S-isomer has similar neuroprotective abilities but is not adopamine agonist (Grunblatt

et al

., 2001b).

In vitro

, APO alsoinhibits mouse striatal MAO-A and -B activities, enzymesinvolved in the enzymatic oxidation of dopamine and conversionof MPTP to MPP

+

, which could also explain its protective effectsagainst MPTP. The mechanisms surrounding the protectiveeffects of R-APO were further explored by microarray analysiscomparing MPTP-treated mice with and without APO-treatment(Grunblatt

et al

., 2001a). APO was found to increase the expres-sion of several protective genes and to decrease expression ofcytotoxic cytokines, confirming earlier studies suggesting thatAPO can also inhibit NF-kappa B activation. However, thesedata collectively suggest that R-APO has many biological effectsother than iron chelation, some of which may contribute to itsmany peripheral side-effects. It also has poor pharmacokineticsand is readily oxidized

in vivo

. In spite of these drawbacks, it isconsidered an effective anti-PD drug especially in patients whono longer respond to levodopa. In such cases, the peripheralside-effects of R-APO are controlled via administration of addi-tional drugs.

Clioquinol (CQ, iodochlorohydroxyquin) has been demon-strated to chelate both ferrous and ferric iron and to resultin decreases in total brain iron levels (Yassin

et al

., 2000). CQ ishydrophobic and freely crosses the blood–brain barrier. Oraladministration has recently been demonstrated to inhibit brainbeta-amyloid accumulation in a transgenic mouse model ofAlzheimer’s disease via its actions as a metal chelator (Bush,2000; Cherny

et al

., 2001). Oral CQ treatment in the range usedin these studies does not elicit any apparent adverse effects on




20

general health or behaviour, unlike chelators currently used astherapy for iron overload conditions which can have severe side-effects. We have recently demonstrated that oral administrationof CQ prior to MPTP administration resulted in a reduction iniron levels concomitant with significantly reduced loss of striataldopamine (unpublished data). CQ was formerly widely used asan oral antibiotic with a favourable safety profile. However inthe 1970s it was withdrawn from the market due to speculationthat it was associated with a subacute myelo-optic neuropathy(SMON) in a group of Japanese patients. CQ was subsequentlyshown to lower levels of brain and serum vitamin B12 (Yassin

et al

., 2000). Although SMON appears to resemble a subacuteaccelerated form of B12 deficiency, a causal relationshipbetween SMON and CQ intake has not been established. More-over, B12 deficiency is easily correctable via B12 supplementa-tion. Results from stage two clinical trials in AD patients takingCQ together with B12 supplementation suggest that the drugis both safe and effective (Bush & Masters, 2001; Ashley Bush,pers. comm.). Our data, though preliminary, suggest that CQmay also be effective as a treatment for PD.

Recently, extracts from green and black tea were demon-strated to provide protection against 6-OHDA-mediated celldeath via prevention of NF kappa-B activation. The protectiveproperties are attributed to the potent iron chelation andantioxidant actions of polyphenols contained in the extracts.Since polyphenols are able to penetrate brain and are naturallyoccurring compounds, they have been suggested to be an import-ant novel class of drugs for treatment of neurodegenerativediseases including PD (Levites

et al

., 2002).Another interesting approach to iron chelation which is just

beginning to be explored is the use of compounds which canundergo biotransformation into iron chelators only under oxi-dative stress. It is possible that iron chelators could also be madeas precursors which are selectively activated by relatively SN-specific enzymes such as TH. Finding a way to target suchcompounds would reduce side-effects associated with theiractivation in other brain regions and systemic loss of iron wouldbe prevented. A number of such compounds have been madeand tested but so far are limited in use due to their inability tocross the blood–brain barrier (Galey

et al

., 2000).

Conclusions

Many lines of evidence suggest a major role for iron in theprogression of PD. Its abnormal assimilation in the brains of PDpatients has been hypothesized to exacerbate oxidative stress,produce endotoxins via unusual dopamine oxidation, and toactivate NF-kappa B-mediated cell death pathways which havebeen implicated in disease progression. Iron has also beensuggested to exacerbate alpha-synuclein aggregation, therebycontributing to PD neuropathology. Iron chelation may offer aneffective therapy for the disease by controlling progression ofthe disease on several fronts. An ideal iron chelator would bebrain-permeant and non-toxic, causing little disturbance of sys-temic iron and having antioxidant properties. At the very least,

incorporating a safe and effective iron chelator into a regimeof drugs currently being used for the therapy of PD mightcomplement their actions and help in lowering their effectivedosages.

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