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An introduction to the free radical hypothesis in Parkinson's disease.

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An Introduction to the Free
Radical Hypothesis in Padanson’s Disease
C. W. Olanow, MD
Iron-induced oxidant stress has been implicated in the pathogenesis of Parkinson’s disease. An increasing body of
evidence now indicates that in Parkinson’s disease the environment within the substantia nigra is conducive to the
formation of cytotoxic free radicals and cell degeneration. Dopamine neurons may be particularly vulnerable because
of the oxidative metabolism of dopamine and the potential of neuromelanin to promote the site-specific accumulation
and reduction of iron. This hypothesis has attracted considerable attention because it opens the way for employing
antioxidant strategies as possible neuroprotective treatment for Parkinson’s disease. Although the concept is appealing,
free radicals have not yet been proven to play a role in Parkinson’s disease, and many important issues remain to be
resolved before the oxidative hypothesis can ultimately be confirmed or refuted.
Olanow CM. An introduction to the free radical hypothesis in Parkinson’s disease.
Ann Neurol 1992;32:S2-S9
The notion that iron-induced oxidant stress contributes
to the pathogenesis of Parkinson’s disease (PD) is a
theme being expressed with increasing frequency and
vigor [ 1-57. This theory postulates that cytotoxic free
radicals generated from iron-catalyzed oxidation reactions may damage biological molecules and lead to cell
degeneration. Free radical mechanisms may initiate cell
damage, develop as a consequence of a primary injury,
or act in conjunction with other cytotoxic processes
[G}. If free radicals contribute to the pathogenesis of
PD, the possibility exists that antioxidant therapy
might slow or stop disease progression. The development of a marker of PD might even permit introduction of antioxidant therapy prior to development of
clinical features and thus dramatically alter the clinical
expression of this disorder. Trials of antioxidant therapies have been initiated in P D [7, 81, and further studies are anticipated. However, although a growing body
of theoretical and experimental evidence has implicated free radicals in PD, no direct or conclusive proof
has yet been obtained. This paper reviews the free
radical hypothesis, examines the existing evidence, and
discusses issues that remain to be resolved.
The Free Radical Hypothesis
Oxidation reactions are essential biological reactions
necessary for formation of high-energy compounds
used to fuel cellular metabolic processes. Oxidation
and reduction (redox) reactions involve the transfer of
electrons and can generate by-products known as free
radicals [l, 91. Free radicals are atoms or molecules
that contain an orbital with an unpaired electron. Most
From the Department of Neurology, and the Department of Pharrnacology and Experimental Therapeutics, University of South Florida, Tampa, FL.
free radicals are unstable, highly reactive species capable of extracting an electron from neighboring molecules to complete their own orbital. Molecules that
donate an electron are by definition oxidized and can
be damaged by this process. The reduction of molecular oxygen involves four electrons and generates the
superoxide radical (02-),
hydrogen peroxide (H,O,),
and the hydroxyl radical (OH) (Fig 1). Free radicals,
such as OH, can react with and damage virtually any
biological molecule, including DNA, essential proteins, and membrane lipids [10-131. In the brain,
where there is an abundance of cellular membranes,
hydroxyl radicals can react with lipids and initiate the
chain reaction of lipid peroxidation, with resultant
membrane damage and cell degeneration (Fig 2). These
reactions are extremely rapid and limited primarily by
the rate of diffusion of the hydroxyl radical, so that
molecules in the immediate vicinity of the formation
of free radicals are at greatest risk. H,02 is not a radical, but it is an oxidizing agent capable of causing tissue
damage. Its major threat lies in its potential to be further reduced and to generate the highly reactive hydroxyl radical.
Oxidation reactions are catalyzed by transition metals such as iron, copper, and manganese, which have a
loosely bound electron and can exist in more than one
valence state. They are able to accept or donate an
electron and thus can promote redox reactions and the
formation of cytotoxic radicals. Recycling of iron from
its oxidized to its reduced state by tissue ascorbate,
glutathione, or dopamine can drive oxidation reactions
and the formation of a cascade of free radicals (Fig 3).
Address correspondence to Dr Olanow, 4 Columbia Dr, #410,
Tampa, FL 33606.
(i)DA + 0 2 + H 2 0
[il) DA + 0 2
Fig 1 . The four-step reduction of molecular 0, to H20. Note
that this sequence of reactions generates the superoxide radical
(O,-),hydrogen peroxide (H202) and the hydroxyl radical
( O H - ) .These reactions are catalyzed by transition metals such
as iron, which provide electrons ( e )at each step as shown.
OH’+ Lipid
+ H20
Lipid radical
Lipid’ + 0 2
Peroxyl radical
Lipid 0;
+ Lipid
Lipid-OOH + Lipid’
Fig 2. The sequence of reactions in which the hydroxyl radical
initiates lipid peroxidation. Note that lipid radicals and peroxyl radicds are farmed a5 intermediates and can perpetuate a
chain reaction that converts lipids to lipid hydroperoxides even
in the absence of a continuing source of hydroxyl radicals. The
chain reaction of lipid peroxidation can damage the structural
integrity of membranes and lead to cell degeneration.
OH’+ OH-
Fig 3. Recycling of iron from its oxidized to its reduced state
can drive oxidation reactions and generate a cascade of cytotoxic
free radicals. These reactions can be promoted by ascorbate, reduced glutathione, or dopamine in tissue.
The likelihood that an oxidation reaction will take
place can be influenced by the regional concentration
of a transition metal. An increase in iron concentration is associated with an increased likelihood that oxidation reactions will occur and that free radicals will
be formed {14, 151. In contrast, iron chelation retards
or aborts the oxidation process 116, 171. Alterations in
the concentration of transition metals have been implicated in several basal ganglia disorders, including Wilson’s disease (copper), parkinsonism (manganese), and
Hallemorden-Spatz disease (iron).
+ 0 2 - + 2H+
NH3 + H202 +
3.4 Dihydroxylphenylacetylaldehyde
+ H202
2GSH+H,O,_ -
+ Fe2+
+ 2H20
OH’+ OH-
+ Fe3+
Fig 4. (A) Metabolism of dopamine by MA0 (i)or by autooxidation (ii).Note that for each mole of dopamine that is metabolized, a mole of H202 is farmed, raising the threat of hydroxyl
radical formation. IB) Clearance of H202 by reduced glutathione (GSH-),thereby preventing the interaction of H,O, with
iron. (C) The Fenton reaction whereby H202 that has not been
cleared can accept an electronfrom Fk+ to form the highly reactive hydroxyl radical. In summay, the oxidative metabolism of
dopamine yields H202 (A), which is normal& cleared b~ glutathione (B) but has the potential to react with ferrous iron to
generate the highly reactive hydroxyl radical (C) .
A number of naturally occurring protective mechanisms have evolved to prevent or limit tissue damage
from oxidation-derived free radicals.
1. The electron transport chain. Ninety-five percent
of molecular oxygen is metabolized within mitochondria by the electron transport chain. Electrons and oxidant species formed in these reactions are tightly
bound so that they do not participate in redox reactions
and can ultimately be cleared (see Fig 1).
2. The electronic structure of molecular oxygen.
Molecular oxygen is a di-radical that in its unexcited
ground state contains two separate orbitals, each housing an unpaired electron with identical spin. Most molecules have orbitals containing two electrons with opposite spin. This difference in rotation creates a spin
restriction and limits the ability of molecular oxygen to
accept electrons directly. For molecular oxygen to accept both electrons, an energy-requiring spin inversion
must take place so the electrons in the reacting molecule have a parallel spin and can fill the vacancies in
the orbitals of the O2 molecule. As a consequence,
molecular oxygen reacts sluggishly with most biological
molecules, which, therefore, do not readily undergo
spontaneous autooxidation.
3. Proteins that bind transition metals. Molecular
oxygen is most likely to react by accepting a single
electron from a transition metal. These reactions are
most likely to occur when a transition metal such as
iron is in a “reactive” state in which it exists in a “free”
or low molecular weight form complexed to ATP or
Olanow: Free Radical Hypothesis in PD
citrate. When a transition metal is bound to a protein
(e.g., ferritin, transferrin, ceruloplasmin) it is in a relatively “unreactive” state and has a limited capacity to
participate in redox reactions {IS]. Iron binding proteins thus serve as an important protective mechanism.
4. Enzymes that clear or prevent formation of oxidant species. Superoxide dismutase (SOD) catalyzes
the conversion of superoxide radical to H,02. Identification of SOD, which presumably evolved to clear
the superoxide radical, provided confirmation of the
existence of free radicals {191. Glutathione peroxidase
and catalase clear H202and prevent its reduction to
OH through the iron-mediated Fenton or HaberWeiss reactions.
5. Free radical scavengers. Compounds such as
ascorbate (vitamin C ) and alpha-tocopherol (vitamin E)
can react directly with free radicals to spare more critical biological molecules or to break the chain reaction
of lipid peroxidation.
Under physiological circumstances, an equilibrium
exists between factors that promote oxidation and protective factors that limit formation of highly reactive
species, such as the hydroxyl radical. A change in the
equilibrium favoring formation of free radicals creates
a state of oxidant stress and can result in damage to
neighboring molecules and cell degeneration. This
mechanism has been implicated in a variety of diseases,
including ischemia-reperfusion in jury, arthritis, cataracts, heart disease, and cancer [201. The free radical
hypothesis in PD postulates that oxidant stress contributes to the underlying cell degeneration responsible
for the disease.
The brain may be particularly vulnerable to oxidant
stress for the following reasons.
1. The brain consumes approximately 20% of total
body oxygen, although it comprises less than 2% of
total body weight.
2. The brain contains large amounts of polyunsaturated fatty acids, which are components of cell membranes and substrates for free radicals and the chain
reaction of lipid peroxidation.
3. The brain is relatively deficient in protective mechanisms compared to other tissues, such as the liver. It
contains almost no catalase and reduced quantities of
glutathione peroxidase, glutathione, and vitamin E.
4. The brain has limited capacity for regeneration.
5. Iron, which can promote reactions that generate
free radicals, accumulates in brain-specific regions (i.e.,
red nucleus, substantia nigra pars reticularis, globus
pallidus) in concentrations that exceed those found in
liver [21). In addition, iron binding proteins may be
relatively deficient in the brain. In plasma, there is a
relative abundance of transferrin and minimal risk of
O H formation. This may not be the case in the brain,
s4 Annals of Neurology Supplement to Volume 32, 1992
because it appears that there is almost no iron binding
capacity in the cerebrospinal fluid despite the presence
of “free” or low molecular weight iron [22).
In addition, dopamine neurons may be at particular
risk for damage by oxidant stress. Dopamine is metabolized either enzymatically by monoamine oxidase
(MAO) or by autooxidation to form H,02 (see Fig 4).
Under normal circumstances, there is an available pool
of glutathione to clear H202and to prevent tissue damage. However, an increase in the steady state concentration of H202could increase the likelihood that it
will react with ferrous iron and generate the highly
reactive hydroxyl free radical. The oxidative metabolism of dopamine thus has the potential to generate
toxic free radicals and to damage dopamine neurons,
particularly under circumstances in which there is an
increase in dopamine turnover, a reduction in the glutathione pool, or an increase in reactive iron. Neuromelanin granules may also confer vulnerability to nigral
neurons by accounting for a site-specific accumulation
and reduction of iron. Melanins can bind trace metals
such as iron {23, 241 and promote reduction of Fe3+
to Fe2+ 1251, in which form iron can promote O H
formation and selectively endanger dopamine neurons.
Evidence That Free Radicals Contribute to
Pathogenesis of PD
An increasing body of evidence has been accumulated
to support the notion that the pars compacta of the
substantia nigra (SNc) is in a state of oxidant stress in
P D and that the environment is conducive to formation
of free radicals. First, lipid peroxidation is increased,
suggesting that lipids have been damaged by free radicals [26]. Second, defense mechanisms appear to be
compromised. Glutathione is reported to be markedly
reduced in PD, particularly in patients with advanced
disease 127, 281. Furthermore, peroxidase enzyme activity and, more specifically, glutathione peroxidase are
said to be reduced in some patients with PD [29, 301.
Third, an increase in mitochondrial-associated SOD
has been observed in the nigra in P D [31]. Increased
levels of SOD could occur in response to an increased
production of 02-.
In the SNc, conversion of 02-to
H202by SOD could aggravate an underlying state of
oxidant stress and encourage formation of O H radicals. Fourth, complex I of the mitochondrial respiratory enzyme chain is reported to be reduced in the
nigra {32, 331, platelets 1341, and muscle [35} of patients with PD. This reduction could impede trapping
of electrons and lead to diminished synthesis of adenosine triphosphate (ATP), necessary for many critical
metabolic reactions, including the generation of glutathione.
Most interest, however, has focused on reports of
increased iron in the SNc of patients with P D because
Free radicals
) ,ln
Complex I
Fig 5 . A theoretical model illustrating how an interplay of complex I , glutathione (GSH),peroxides, and iron could lead t o a
cycle generating free radicals and causing neuronal damage.
(Adaptedfrom is).)
of the critical role that this metal has in oxidation reactions. In its reactive form, iron promotes redox reactions and increases the likelihood that spontaneous autooxidation will occur and that cytotoxic radicals will
be formed [lS]. In contrast, iron chelation retards
oxidation reactions and also diminishes the likelihood of free radical damage [16, 171. Increased iron
was first reported in the brain of patients with P D by
Earle [36], who used x-ray fluorescent spectroscopy.
Subsequently, numerous investigators, using a variety
of imaging and analytic techniques, detected increased
iron localized to the SNc in patients with P D [37-401.
This finding may be particularly relevant in view of a
report that ferritin, the primary binding protein for
iron in the brain, is reduced in the SNc of patients
with PD [4 1). This observation implies that iron in the
SNc of patients with PD exists in a non-protein bound
or reactive form capable of promoting formation of
cytotoxic free radicals. This interpretation is supported
by the observation that levels of the antioxidant ion
zinc are also increased in the nigra of patients with PD,
presumably as a response to an iron-induced oxidant
stress 138). The potential importance of iron as a neuronal toxin is illustrated by studies which demonstrate
that iron chelators diminish the toxicity of 6-hydroxydopamine [42] and that iron infusion into the SNc
induces a dose-related degeneration of nigral neurons
[43, 44). That oxidant stress accounts for neuronal
damage in the iron infusion model is suggested by
experiments in which coadministration of the ironbinding protein transferrin attenuates neuronal damage
This evidence supports the concept that oxidant
stress contributes to the pathogenesis of PD. One
could envision how an interplay between complex I,
glutathione, peroxide, and iron could result in a cycle
in which free radicals are formed and neuronal damage
occurs (Fig 5). This concept could account for oxidant
stress developing in a given patient as a result of different etiologies acting alone or in combination. O n the
basis of this theory, clinical trials have been designed
to test antioxidant agents that might interfere with free
radical damage as possible neuroprotective therapy
r7, 8). These studies demonstrate that the selective
MAO-B inhibitor deprenyl delays development of disability in otherwise untreated patients with PD, possibly by diminishing peroxide formation due to the
MAO-B oxidation of dopamine. Although a symptomatic mechanism might account for part or all of the
observed clinical effects {46), the findings are consistent with the hypothesis that free radical mechanisms
contribute to cell death in PD. Deprenyl, however,
does not stop the progression of PD, possibly because
it does not prevent the formation of peroxides formed
by the MAO-A oxidation of dopamine. If free radicals
do have a role in the pathogenesis of PD, it is likely
that more potent antioxidant agents can be developed
that will provide more profound neuroprotective effects. Although this is a highly desirable goal, many
issues still need to be explained before the concept of
iron-induced oxidant stress can be accepted as contributing to the pathogenesis of PD.
Much of the current interest in the free radical hypothesis is based on the finding of increased iron in the
SNc of patients with PD because of its known role in
promoting oxidant stress. However, surprisingly little
is known about brain iron. Iron is not found in the
brain at birth. It is first detected by Perls' stain and
magnetic resonance imaging during the first decade and
reaches adult levels at approximately age 20 years [2 1,
471. Levels remain relatively constant for the next several decades and may increase again in the later years
of life. Iron is believed to enter the brain bound to
transferrin by way of transferrin receptors [481. Once
in the brain, iron is primarily stored in oligodendroglia
bound to the storage protein ferritin [49] and accumulates in high concentrations in selected brain regions.
Brain iron appears to be remarkably stable. In adults,
the blood-brain barrier is closed to meaningful penetration of iron, and changes in the peripheral pharmacokinetics of iron do not influence brain iron concentrations.
It is not clear, however, why iron has ready access
to the brain in early life but not in the adult, why iron
accumulates in brain-specific regions that are remote
from areas with the highest concentrations of transferrin receptors [SO}, why iron accumulates in concentrations that appear to be far in excess of those required to fulfill its known physiological functions, or
Olanow: Free Radical Hypothesis in PD
why the capacity to maintain iron in a nonreactive form
appears to be less in brain than in plasma.
It is not clear whether iron accumulates in a reactive
or nonreactive form. The accumulation of iron per se
may not be a risk for oxidant stress if the iron is bound
to a protein such as ferritin so that it is in a nonreactive
form and does not participate in redox reactions. O n
the other hand, an increase in “reactive” or low molecular weight iron that can promote oxidation reactions
may be of critical importance. The finding of decreased
ferritin in PD implies that iron is present in a low
molecular weight form that can promote oxidation reactions C411. However, a monoclonal antibody to
splenic ferritin was used in this study 1411 and was
not confirmed in another study using a monoclonal
antibody to hepatic ferritin 1511. It is also not certain
whether patients in the latter study had PD or multisystem atrophy. Additional studies are needed to clarify
this issue and to definitively determine whether iron is
present in a reactive or nonreactive form in normal and
pathological states.
It is not clear how iron accumulates in PD. Alterations in the blood-brain barrier, bleeding with release
of iron from degraded hemoglobin, impaired clearance, and alterations in transport or endogenous redistribution have all been considered, but direct evidence
supporting any of these mechanisms is lacking.
Information on the precise anatomical distribution
of iron is also needed. Measurements of iron in the
SNc to date have largely relied on bulk analysis.
Knowledge of the cellular and subcellular distribution
of iron would be preferable, but techniques that have
been employed to date lack sufficient sensitivity. There
are suggestions that iron both does and does not accumulate within neuromelanin granules, and conflicting
results have been reported even using the same rechnique C37, 52) (Jellinger K. Personal communication,
1991).Recently, studies using both x-ray microanalysis
and the Laser Microprobe Mass Analyzer (LAMMA)
have shown that iron does significantly accumulate
within neuromelanin granules of SNc neurons in patients with PD 1531. These findings support the notion
that neuromelanin may account for the site-specific accumulation of trace metals such as iron within the SNc.
Because neuromelanin exists in different forms, it is
possible that neuromelanin in patients with P D and
control subjects may differ in their capacity to bind
metals and to promote redox reactions 1541.
Luborato?y Evidence of Oxidant Stress
Evidence that free radical damage actually takes place
in the nigra of patients with PD is based on a single
study that used indirect evidence of lipid peroxidation
{26]. This interpretation is based on the findings of an
increase in malonyldialdehyde (a stable intermediate
formed during lipid peroxidation) and a decrease in
S6 Annals of Neurology
Supplement to Volume 32, 1992
polyunsaturated fatty acids (a substrate for free radicals). The effect of death and autolytic change on these
parameters has not yet been clearly defined. Confirmation of increased lipid peroxidation using these and
other more refined techniques is required. Furrhermore, free radical damage need not be exclusively or
even primarily confined to lipids. Evidence of oxidative
damage to other molecules such as proteins and DNA
must also be sought.
Findings of decreased glutathione in patients with
PD must be interpreted in light of new studies in which
it is suggested that glutathione levels decrease rapidly
following death 15 5). Future studies of glutathione will
have to control not only for the time from autopsy to
study but also for the time from death until freezing.
A determination of the levels of oxidized and reduced
glutathione might also be valuable in trying to define
oxidant stress. The changes reported in peroxidase and
glutathione peroxidase enzyme activity were slight, not
present in all individuals, and of questionable relevance. Although increased levels of zinc may indicate
a reaction to oxidative stress, no change in nigral levels
of ascorbic acid 1281 or vitamin E 1561have been found
in PD to indicate compensatory change in these protective systems.
The deficiency in complex I in the nigra of patients
with PD has received much attention because this
finding has also been observed in N-methyl-4-phenyl1,2,3,6-tetrahydropyridine(MPlT)-induced parkinsonism [57}, and because a decrease in complex I could
lead to free radical formation. However, PD families
with a mitochondrial pattern of inheritance have not
been found, other mitochondrial disorders do not appear to occur with greater frequency in PD, and, at
least with respect to platelets and muscle, the findings
appear to be nonspecific [58} and not universally reproducible 1593. Furthermore, mitochondrial DNA accumulates mutations approximately 10 times faster
than nuclear DNA and is particularly vulnerable to
injury from toxins as well as free radicals C601. Using
the polymerase chain reaction technique, a deletion of
approximately 5,000 base pairs in mitochondrial DNA
has been observed in the corpus striata of patients with
PD [bl]. This deletion, however, was also found in a
group of older nonparkinsonian patients using the
same technique and was not detected in another group
of patients with PD using restriction endonucleases
t62). It remains unclear whether complex I dysfunction is a consistent feature of PD and whether it contributes to the cause or ensues as a result of the degenerative process.
Are Changes in the Nigra Primay or Secondary?
Iron accumulation, glutathione deficiency, and reduction in complex I could all result from, rather than
cause, cell degeneration. Glutathione and complex I
levels would be expected to decrease as a consequence
of significant nigral cell loss. Signal hypointensity consistent with iron accumulation has been observed with
magnetic resonance imaging in a variety of degenerative disorders, including multisystem atrophy, amyotrophic lateral sclerosis, chorea, and multiple sclerosis
1631, and elevated iron levels in the nigra may not be
specific to P D 164). Still, Hirsch and colleagues 140)
found an increase in nigral iron in patients with PD
but not in those with progressive supranuclear palsy,
in whom comparable neuronal degeneration occurs,
suggesting that iron accumulation may not simply be a
consequence of a degenerative process. Regardless of
the primary etiological or pathogenic mechanism, an
environment in which there is increased iron, reduced
glutathione, and reduced complex I could encourage
formation of free radicals and pose a threat to the continued survival of residual dopamine neurons.
Does Deprenyl Act by a Protective Mechanism?
Deprenyl has been clearly and unequivocally demonstrated to delay the development of disability necessitating administration of levodopa in previously untreated patients with PD. This observation is consistent
with a protective mechanism; however, wash-in studies
demonstrate symptomatic effects that may mask underlying disability and account for some or all of the effect
observed 17). Deprenyl might be expected to provide
symptomatic effects by increasing striatal dopamine, by
way of its amphetamine metabolites, or through dopaminergic effects induced by increased levels of phenylethylamine 1461. A clear demonstration that deprenyl
has a neuroprotective effect would provide strong support for the free radical hypothesis.
Does Kyodopa Accelerate Degeneration of Residual
Dopamine Neurons?
Levodopa therapy, by way of its decarboxylation to
dopamine, could increase peroxide formation and promote free radical damage to residual dopamine neurons in PD. However, levodopa administration to patients with P D is associated with marked improvement
in both morbidity and mortality 1651, and high-dose
levodopa administration has not been demonstrated to
adversely affect nigral neurons in normal rats, mice, or
nonparhnsonian humans 166-68). Still, administration
of levodopa to a parkinsonian patient in whom there
may exist a state of oxidant stress and compromised
defense mechanisms may be very different than its administration to normal control subjects. Furthermore,
improvement in parkinsonian morbidity and mortality
due to the symptomatic effects of levodopa does not
preclude levodopa having an adverse effect on surviving neurons: Dopamine has been shown to be toxic to
dopamine neurons in tissue culture 169). Both levodopa administration and increased dopamine turnover
induce a state of oxidant stress, as evidenced by an
increase in oxidized glutathione 170, 71). In addition,
depletion of dopamine by MPTP protects against ischemia-induced cell death in the striatum, probably by
diminishing free radical formation generated by the
metabolism of dopamine 1721.
Patients treated with levodopa as primary therapy
have more adverse effects than those who receive dopamine agonists, which do not undergo oxidative metabolism 1731. It is currently believed that these adverse effects are a function of the number of remaining
dopamine terminals and their capacity to store dopamine 1741. The increased incidence of adverse effects
associated with levodopa might reflect accelerated degeneration of dopamine terminals compared to patients
treated with dopamine agonists 1751. That dopamine
agonists may have a protective effect on dopamine neurons is also suggested by studies in which rodents fed
the dopamine agonist pergolide had significant inhibition of age-related decline in nigral dopamine neurons
and striatal dopamine terminals in comparison to pairfed control rodents 176). The authors hypothesize that
pergolide stimulates dopamine autoreceptors, thereby
decreasing dopamine turnover and reducing free radicals generated from the metabolism of dopamine. Although there is no conclusive proof that levodopa
harms dopamine neurons, this issue is not resolved. A
clear determination of whether levodopa has adverse
effects on dopamine neurons in patients with PD is of
paramount importance to neurologists who rely on
levodopa as the primary form of symptomatic therapy.
Other Issues
Even if the free radical hypothesis is ultimately confirmed, there are several factors that must still be
considered. (1) What factors initiate oxidant stress?
(2) Why are some cells more vulnerable than others,
or, alternatively, why are some cells relatively protected? (3) How does the free radical hypothesis account for the degeneration of nondopaminergic
A theoretical and experimental foundation can be provided for the notion that iron and oxidant stress contribute to the cell degeneration that underlies PD, but
many issues remain to be resolved before this hypothesis can be confirmed. In this supplement, articles address the scientific basis of the free radical hypothesis,
the existing evidence implicating free radical mechanisms in PD, and the therapeutic implications. Continued laboratory studies and clinical trials are necessary
to confirm or refute the role of iron and oxidant stress
in the pathogenesis of PD. The potential to introduce
antioxidant agents as neuroprotective therapy lends an
urgency to this pursuit. In this endeavor, it is wise to
Olanow: Free Radical Hypothesis in PD
recall that some antioxidants can have undesired prooxidant effects [77}, that free radicals may have an important role in physiological functions, and that nonspeclfic inhibition of free radical formation may have
adverse consequences [78}.
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