LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
Antioxidant Therapy in
Parkinson's Disease
J. David Grimes, Mohamed N. Hassan and Jay Thakar
ABSTRACT: It is postulated that endogenous oxidative mechanisms are a major factor in the continuing death of
dopaminergic neurons and the progression of Parkinson's disease. Scientific evidence in support of, and negating, the
free radical auto-toxicity and dopamine toxicity concepts is reviewed. There is conflicting evidence whether free
radicals are involved in the toxicity of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and attempts to prevent
the toxicity of MPTP with antioxidant therapy have had variable results. The oxidation of dopamine by monoamine
oxidase produces toxic metabolites however animal studies with high dose longterm levodopa and MPTP have failed
to show clear evidence for autoxidation. Firm supportive evidence is obtained from the monoamine oxidase B
inhibitor experience which demonstrated a block of the toxicity of MPTP in animals and probable prolongation of the
course of human Parkinson's disease.
The scientific data available is inconclusive but there is significant hope of retarding progressive catecholaminergic
neuron degenerative changes by augmenting the free radical scavenging system with antioxidants (such as Vitamin E)
and slowing catecholamine oxidation by monoamine oxidase B inhibition. Careful clinical trials with these agents
must be performed.
RESUME: La therapie par les anti-oxidants dans la maladie de Parkinson. On a postule que les mecanismes oxidatifs
endogenes sont un facteur important dans la perte graduelle de neurones dopaminergiques et dans la progression de la
maladie de Parkinson. Nous revoyons les donnees scientifiques pour et contre les concepts d'auto-toxicit6 des
radicaux libres et de la toxicity de la dopamine. Les observations sont contradictoires en ce qui a trait a l'implication
des radicaux libres dans la toxicite du l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) et les tentatives de
prevention de la toxicite du MPTP par les anti-oxidants ont eu des resultats variables. L'oxidation de la dopamine par
la monoamine oxidase produit des metabolites toxiques; cependant, des etudes chez l'animal traite' a long terme avec
des doses elevens de levodopa et de MPTP n'ont pas montre' de fagon probante qu'il y a effectivement auto-oxidation.
L'utilisation experimentale d'un inhibiteur de la mono-oxidase B, qui met en evidence un blocage de la toxicity du
MPTP chez les animaux et qui prolonge probablement la duree devolution de la maladie de Parkinson, supporte cette
theorie.
Les observations scientifiques que nous possedons actuellement ne nous permettent pas de trancher la question.
Cependant, nous croyons qu'il y a bon espoir d'arriver a retarder la progression de la degen6rescence des neurones
catecholaminergiques en augmentant le systeme de vidange des radicaux libres par l'utilisation des anti-oxidants (tel
la vitamine E) et en ralentissant l'oxidation des catecholamines par l'inhibition de la monoamine oxidase B. On doit
done proc6der a des essais cliniques minutieux avec ces substances.
Can. J. Neurol. Sci. 1987; 14:483-487
Endogenous oxidative mechanisms may contribute to death
of dopaminergic neurons and the development and progression
of Parkinson's disease. The focus for clinical pharmacology
research in parkinsonism is changing to include preventive
therapy. The limitations of levodopa therapy are well known1
and an even greater concern is that the drug, or its metabolites,
may enhance cell dysfunction.2 The selective neurotoxin
1 -methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) has generated an explosion of new knowledge about dopaminergic
neurons and their normal and abnormal biochemistry.34'56
This new focus on exogenous toxins has also rekindled interest
in, and made past information more relevant, regarding endogenous cell autotoxicity.7,8
The increased dopamine synthesis demanded of surviving
nigral neurons in the parkinsonian brain produces oxy-radicals
such as superoxide which may overwhelm the protective scavenging capacity of the cell and attack cell membranes through
peroxidation of polyunsaturated fatty acids.8 It has been shown
that free radical protective enzymes are reduced in Parkinson's
disease.910 The free radical autotoxicity concept is supported
by a number of other scientific observations.
Manganese, 6-hydroxydopamine and MPTP may all cause
neuronal damage via free radical producing mechanisms."12
Cigarette smoking produces protective oxidative reducing
agents. 813 Deficiency of Vitamin E causes intraneuronal
lipofuscin deposition and increased lipid peroxides in ani-
From the Parkinson's Disease Clinic & Laboratory, Ottawa Civic Hospital
Reprint requests to: Dr. J.D. Grimes, Ottawa Civic Hospital, 1053 Carling Ave., Ottawa, Ontario, Canada Kl Y 4E9
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THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
ma | s i4.i5.i6 a n c j j t a n c j o t n e r antioxidants such as ascorbic acid,
beta carotene and N-acetylcysteine have had varying protective effects on MPTP induced striatal dopamine and glutathione
loss. 1 7 1 8 Monoamine oxidase inhibitors (MAO B type), are
shown to protect animals against MPTP toxicity. 19
The oxidation of dopamine by monamine oxidase also produces toxic metabolites." 1 2 ' 2 0 ' 2 1 The aged brain has increased
dopamine turnover 7 and increased monoamine oxidase activity22 and it has been shown that L-deprenyl (a selective MAO B
inhibitor) may retard the course of human Parkinson's disease
and allow a reduction in levodopa dosage. 23
This scientific evidence, which at present is inconclusive,
raises exciting hope of retarding these catecholaminergic neuron degenerative processes in patients who either are at risk for
parkinsonism or who have early disease. Augmenting the free
radical scavenging system with antioxidants (such as alpha
tocopherol) and inhibiting catecholamine oxidation with deprenyl
are two therapeutic approaches that are now undergoing clinical evaluation.
SCIENTIFIC DATA IN SUPPORT OF THE AUTOTOXICITY CONCEPT
Endogenous Toxins
The evidence to support the autotoxicity, oxy-radical concept has slowly accumulated over the past 20 years. Barbeau
and Calne have helped summarize and focus this information
into interesting working hypotheses with treatment implications for Parkinson patients. 7 ' 8 ' 24 It is generally accepted that
catecholamine metabolism in dopaminergic neurons produces
free radicals. A free radical is defined as an atom or group of
atoms with an unpaired electron occupying an outer orbit. They
exist for fractions of a millisecond and are difficult to study.
Free radicals are produced as oxygen is utilized and are generally present in low concentrations. They will however damage a
cell if their concentration exceeds the protective scavenging
capacity of the cell. It is being suggested that death of dopaminergic
neurons in the substantia nigra and locus ceruleus results in
reduced dopamine in the striatum and that feedback mechanisms will demand increased dopamine synthesis and turnover
in remaining brainstem neurons with enhancement of free radical production. The basic concept then becomes one of a selfsustaining and progressive degenerative process of the catecholaminergic system as a result of exposure to free radicals
over many years.
The most important radical is superoxide and it and hydrogen
peroxide attack the polyunsaturated fatty acids in cell membranes to form lipid hydroperoxides which react with other
membrane lipids to initiate a chain reaction of lipid peroxidation.25
There are cellular defenses which limit free radical damage.
Superoxide dismutase scavenges superoxide radicals and catalase and glutathione peroxidase reduce hydrogen peroxide's
damaging effects. In addition, reactive soluble reducing substances such as alpha tocopherol, ascorbic acid, beta carotene
and uric acid attempt to maintain a balance between free radical
production and consumption. 26 It has been shown that the
concentrations of the protective enzymes, superoxide dismutase,
catalase and glutathione peroxidase are reduced in the substantia
nigra of parkinsonian patients. 9 1 0 Other environmental factors
which may contribute to the free radical excess include; nonsmoking, low consumption of reducing agents, and exposure to
metal ions. Graham" has suggested that manganese neurotoxicity and Parkinson's disease have a common pathogenesis that
includes progressive neuronal injury from the oxidation products of dopamine. It has been shown that 6-hydroxydopamine
also causes cell damage by the release of free radicals. 27
Poirier 28 has shown that other trace metals, particularly iron,
which are in high concentration in the substantia nigra, enhance
dopamine autoxidation and the toxicity of MPTP. Magnetic
resonance imaging (MRI) has confirmed the increased basal
ganglia iron content in living subjects. 29
There is conflicting evidence that free radicals are involved
in the toxicity of MPTP. Cells containing neuromelanin (which
exists as a redox-polymer) are especially sensitive to MPTP's
neurotoxic effect. Its potent metabolite MPP + resembles paraquat which induces toxicity by the generation of a superoxide
radical. 12 Studies have however shown that MPTP is a very
poor generator of oxygen radicals and causes very little lipid
peroxidation in subcellular fractions. 30 Some workers have
shown that antioxidants such as ascorbic acid, alpha tocopherol,
beta carotene and N-acetylcysteine protect dopaminergic neurons from MPTP toxicity. I7 ' 31,32 ' 33 Others have shown that
the same antioxidants fail to inhibit depletion of striatal dopamine by MPTP. 18
Dopamine itself may be neurotoxic; 20 it undergoes spontaneous autoxidation to produce the toxic triad of reduced oxygen,
hydrogen peroxide and hydroxyl radicals plus a quinone. Dopamine is normally metabolized to homovanillic acid. The presence of reactive, partially reduced oxygen molecules promotes
the oxidation of catecholamines to quinones. It was suspected
that MPTP may induce toxic quinone production from dopamine however animal studies have not supported the dopamine
autotoxicity theory. 34 The concern that dopamine itself has
neurotoxic properties 20 has raised suspicion that exogenous
levodopa may hasten the progression of Parkinson's disease. 2
These clinical concerns have not been supported by pathological studies of animals treated with longterm high dose levodopa. 35 ' 36 Quinn has recently reported preservation of the
substantia nigra in a patient without Parkinson's disease who
was treated for four years with levodopa. 37 It has also been
suggested that some endogenous dopamine may be converted
to the neurotoxin 6-hydroxydopamine and this may be part of
amphetamine toxicity. 38
Neuromelanin
The study of neuromelanin adds a further interesting dimension to the auto-toxicity discussion as its accumulation may
promote cellular dysfunction and degeneration. 12 Brain areas
with more neuromelanin are more sensitive to the cytotoxic
effect of MPTP. 39 However there are pigmented brainstem
nuclei that are not damaged by MPTP. 34 Neuromelanin was
initially thought to be a slowly accumulating waste product of
catecholamine metabolism. Neuromelanin contains quinones
and hydroxyquinones and is formed by the autoxidation and
polymerization of tyrosine and dopamine and its accumulation
is enhanced by deficient cellular defense mechanisms. Insufficient reserves of antioxidants (including Vitamin E) result in
increased collection of lipopigments 40 and Bannon has suggested that MPTP may decrease glutathione in the substantia
nigra and results in more dopaquinone formation and subsequent conversion to melanin. 41
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LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
Smoking
Epidemologic studies have suggested a protective effect of
cigarette smoking on the risk of Parkinson's disease. I3 Smoking
facilitates dopamine release and dopaminergic neural transmission throughout the nervous system and in this way might
reduce the clinical expression of parkinsonism. A more relevant consideration is that of Calne and Langston 8 that smoking
results in an increase in protective reducing agents such as
carbon monoxide and this increase in reduction potential traps
free radicals and protects against oxidative mediated neuronal
damage. It has also been suggested that smoking may induce
protective enzyme systems (cytochrome P450) in the liver that
would enhance the elimination of toxic compounds.
Environmental and Aging Factors
The time to initiate parkinsonism protective therapy has
interesting considerations. Hornykiewicz 42 noted that mild,
clinicallyjust detectable symptoms of parkinsonism are associated with more than 80 per cent loss of striatal dopamine. It is
also accepted that the number of neurons in the substantia nigra
decreases with age and is most pronounced in patients with
Parkinson's disease. 43 If endogenous or environmental factors
are important in this slow degenerative process then consideration must be given to early rather than later life so that preventive therapy could be more effective.44 The practical implementation of early life therapy to retard dopamine neuronal cell
dysfunction is obviously not possible at present but interesting
theories regarding rural environment and well water use have
been proposed. 45 Increased age has been shown to be an important factor in increasing the susceptibility of animals to the
toxic effects of MPTP 46 and pathological changes more suggestive of Lewy bodies have now been seen in older MPTP treated
monkeys. 47
The possibility that idiopathic Parkinson's disease may be
caused by repeated exposure to one or more endogenous or
exogenous MPTP-like compounds has produced a number of
interesting theories. Ramsden, 48 Fellman 49 and Testa 50 have
commented on the possible production of toxic endogenous
methylpyridium compounds from tryptamine and catecholamines and Barbeau 51 has suggested that Parkinson patients
have an inherent susceptibility to environmental toxins. The
search for exogenous neurotoxins continues with interesting
findings such as that of the food neurotoxin (false sago palm
seed) in motor neuron disease of Guam. 52
Vitamin E
Vitamin E acts as a lipid soluble antioxidant in the nervous
system; it inhibits the oxidation of unsaturated fatty acids. It is
stated that the antioxidant effect of tocopherols is their major
biological activity. 53 Vitamin E contains a 6-hydroxychroman
ring which reacts with free radicals and a 16carbon hydrophobic
side chain which promotes lipid solubility. Eight compounds
have been isolated with Vitamin E reactivity and alpha tocopherol has the greatest antioxidant potency as a free radical
scavenger. 54 Vitamin E appears to be located in cell membranes
close to enzymes that produce free radicals. 55,56 No clinical
evidence of parkinsonism or basal ganglia pathological changes
have been documented in human Vitamin E deficiency. Clinically significant Vitamin E deficiency is only seen in fat malabsorption disorders and then manifests with retinal, sensorimotor
and cerebellar defects which are halted with replacement
Volume 14, No. 3 (Supplement) — August 1987
In animals, Vitamin E deficiency causes
therapy. 5 7
intraneuronal lipofuscin accumulation 1415 and this can be avoided
by treatment with alpha tocopherol, selenium and reduced
glutathione. 40 There are also age related increases in lipid peroxide formation which may be reversed with Vitamin E. 16
MONOAMINE OXIDASE INHIBITION
There is considerable evidence to support the proposal that
inhibition of brain monoamine oxidase (MAO) will slow the
progression of dopaminergic cell dysfunction. The oxidation of
dopamine by MAO can produce toxic metabolites including
6-hydroxy dopamine, quinones, and hydrogen peroxide.II-2U-2''-7
The aged brain has an increase in monoamine oxidase activity
and this becomes significant when one considers the requirements for increased dopamine from this reduced number of
nigral neurons. 2 2 Clinical studies have demonstrated that
L-deprenyl, a selective MAO B blocker may prolong the course
of human Parkinson's disease and reduce the requirement for
levodopa. 23 The brain contains predominately monamine oxidase B and one autopsy study has confirmed that there is
almost complete inhibition of MAO B in patients treated with
deprenyl and levodopa. 60 MPTP induces parkinsonism in many
animal species and this is prevented by pre-treatment with
monoamine oxidase B inhibitors. 61
CLINICAL CONSIDERATIONS
It is important that large, carefully documented clinical trials
be completed to evaluate the antioxidant, auto-toxicity concept.
The success of such trials will be completely dependent on well
defined clinical parameters. The best model is likely to select
patients with early Parkinson's disease, treat them with antioxidant therapy, and document that the rate of disease progression
and requirement for levodopa therapy are both delayed as
compared to previous experience. Spinal fluid homovanillic
acid levels may be followed as a measure of dopamine metabolism but there are no studies now available to monitor free
radical activity and lipid peroxidation changes.
Vitamin E is an excellent choice as an antioxidant. It is more
potent than ascorbate or beta carotene. 62 The doses used in
malabsorption states average 100 mg per kilogram per day and
the recommended daily dietary allowance is 10-30 mgperday. 5 3
Therefore doses of one to three grams daily should be more
than sufficient as antioxidant therapy. No human trial has
yet been published using Vitamin E as Parkinson preventive
therapy.
Experience world-wide with Deprenyl indicates that it is a
safe drug, which at low dosage is free of the "cheese" effect,
and that a dose of 10 mg daily inhibits 95% of MAO B activity. 63
Some concerns have however surfaced; Yahr 64 found a
number of adverse effects including gastric bleeding and the
drug is metabolized to methamphetamine which raises potential toxicological considerations.
DISCUSSION
The above scientific data raises both positive and negative
points relating to the use of antioxidant therapy for the prevention of progression of Parkinson's disease.
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THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES
The positive points in favour of this theory will be reviewed
first. The excess oxy-radical auto-toxicity concept while not
conclusive has a reasonable scientific basis. The fact that free
radical protective enzymes are reduced in the brain of Parkinson patients and the support for the free radical theory gained
from the manganese and 6-hydroxydopamine stories is of note.
Cigarette smoking may increase reducing agents and have a
protective effect. Vitamin E is a known antioxidant and free
radical scavenger. A deficiency of Vitamin E causes intra neuronal lipofuscin accumulation which may promote neuronal
dysfunction. Firm evidence for the endogenous oxidative damage theory is derived from the monoamine oxidase data. Monoamine oxidase is increased in the older brain. Monoamine oxidase
B inhibitors block the toxicity of MPTP, and deprenyl may
prolong the course of human Parkinson's disease.
A number of points that are not supportive of the antioxidant
therapy concept come out of this review. It is by no means
definitely clear that the free radical auto-toxicity concept is a
factor in the progression of parkinsonism or aging of cells in
general.
The variable protective effects of antioxidants against MPTP
induced neurotoxicity is of concern. It is not at all clear that free
radicals are involved in the toxicity of MPTP and MPTP has
caused minimal lipid peroxidation. The evidence for endogenous dopamine and exogenous levodopa toxicity is equivocal.
The role of neuromelanin is indefinite, some pigmented brainstem
nuclei are not sensitive to MPTP and some animals (cat and
mouse) who do not have neuromelanin have shown evidence of
neurotoxicity with MPTP. Despite all of the interest in toxins
and Parkinson's disease, no clear environmental toxin has yet
been implicated. Vitamin E has been proposed as preventive
therapy for parkinsonism despite a lack of basal ganglia pathological changes being shown with Vitamin E deficiency and the
fact that no definite studies using Vitamin E as preventive
therapy have yet been published.
Despite this inconclusive data the possibility of retarding the
progression of Parkinson's disease is real and exciting and must
be pursued. The agents being considered are safe, and careful
clinical trials must be done to evaluate the therapeutic benefit
of augmenting the free radical scavenging system with antioxidants and retarding catecholamine oxidation by inhibiting monoamine oxidase B activity.
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