Preventive Medicine and
Nutrition
www.pcrm.org
Functional
Therapeutics in Neurodegenerative Disease
David Perlmutter, M.D.
Abstract
Genetic, toxic, nutritional, traumatic, and
lifestyle models have been proposed as playing major roles in the
etiology of various neurodegenerative diseases. A model whereby
genetically predisposed individuals manifesting demonstrable
hepatic detoxification flaws enhancing the neuro-toxic effects of
xenobiotics leading to neuronal mitochondrial failure unifies
these seemingly disparate theories into an integrated model of
neurodegenerative diseases.
Foreword by
Jeffrey S. Bland, Ph.D.
Dr. David Perlmutter has accomplished a very
courageous task in his monograph Functional Therapeutics in
Neurodegenerative Diseases. He has crossed the disciplinary
boundaries from the comfort of his profession as a board-certified
Neurologist to put together a very compelling integrated model for
the development of neurodegenerative diseases.
As he points out in the monograph, this
model opens the door for a number of new therapies for these
disorders which historically have had few therapeutic options.
Dr. Perlmutter couples the perspectives of
both a clinical and experimental neurologist to help us understand
the revolution that is occurring in the emerging treatment of
neurological disease. This revolution is built upon the concepts
of molecular medicine as first described by Linus Pauling in 1949.
Flint Beal, M.D., Ph.D., an experimental
neurologist at Harvard University Medical School, has echoed Dr.
Perlmutter�s vision of the future of neurology in his paper,
Aging, Energy, and Oxidative Stress in Neurodegenerative Disease.1
The model that Dr. Perlmutter advances is an
integrated model of neurodegeneration coupling genetics,
environment, nutrition, lifestyle, and infection. The theme that
Dr. Perlmutter develops is that many exposures can initiate an
upregulation of the immune system, which in response releases the
inflammatory cytokines. These in turn upregulate the expression of
the immune inducible form of nitric oxide synthase. The increased
production of nitric oxide in the microglia triggers the depletion
of neuronal ATP which in turn increases the activity of xanthine
oxidase. This enzyme converts purines to uric acid in the neuron
with the production of the reactive oxygen species, superoxide.
Superoxide then reacts with nitric oxide to yield peroxynitrite,
which results in death of the cell.
Many agents can trigger this cascade in
genetically susceptible individuals including bacterial
lipopolysaccharides from enteric bacteria, toxic metals and
pesticides, food and environmental antigens, stress responses
mediated through the pituitary-thyroid-adrenal axis, and chronic
infection.
Recently it has been shown that individuals
who die of Alzheimer�s disease have a very high gene penetration
of apo E4 and a chronic infection with herpes simplex Type 1 (cold
sores). Only when both genetic factor apoE4, and the chronic
infection are present simultaneously does Alzheimer�s disease
result.2
Dr. Perlmutter points out that genetic
impairment in detoxification ability may also render individuals
more susceptible to neurotoxic effects of xenobiotics. The field
of pharmacogenics has recently emerged as a discipline of science
and medicine focused upon better understanding of how to assess
individual detoxification ability.3 It has been
recently reported that older-age individuals who have reduced
detoxification ability may be at risk to Parkinsonism symptoms
from the use of the drug metaclopramide (e.g., Reglan�
).4 Defects in sulfoxidation and Phase II
glucuronidation and glutathione conjugation have all been
identified as risks to neurodegenerative disease.
As Clough has pointed out there is generally
a lapse of thirty years or more from the onset of accelerated
neurodegeneration until the symptoms of diseases such as
Alzheimer�s or Parkinson�s are diagnosed.5 As he points
out, this is the period when �neuroprotective therapy� can be
introduced, if the physician is aware of these functional
neurological changes.
Dr. Perlmutter helps us to understand better
how to ask the right questions concerning the early-stage
development of neurodegeneration and provides clues as to its
remediation from the answers to these questions.
As Cohen has observed, with many of the
neurodegenerative diseases, �the brain is on fire� due to the
uncoupling of neuronal mitochondrial function and the release of
oxidants.6 Shifts to anaerobic metabolism often occur
with accumulation of cis-aconitate, succinate, and lactate in
biological fluids. It is interesting that this situation is
observed not only in neurodegenerative diseases, but also with
less severity in chronic fatigue syndrome, fibromyalgia,
multichemical sensitivity, and individuals with Gulf War Syndrome.7
It is possible that the integrated mechanism for neurodegenerative
disease described by Dr. Perlmutter in this monograph applies to
these other conditions/syndromes as well.
Dr. Perlmutter�s contribution toward our
understanding of the origin of neurodegenerative diseases
converges with the model for the origin of chronic fatigue
syndrome published by Martin Pall, Ph.D., from the Program in
Basic Medical Sciences, Washington State University.8
Dr. Perlmutter offers us a most provocative
model for many disorders of the central nervous system. More
importantly, this model directs the clinician toward new therapies
which hold the promise of improving therapeutic efficacy with a
minimal risk to adverse drug reactions.
It is a great privilege to share the field
of functional medicine with Dr. David Perlmutter as a colleague
and fellow seeker for the understanding the origin of degenerative
disease.
Jeffrey S. Bland, Ph.D.
Institute for Functional Medicine
References for Dr.
Bland
1. Beal MF. Aging, energy and oxidative stress in
neurodegenerative diseases. Ann Neurol 1995;38(3):357-366.
2. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson
GA. Herpes simplex virus Type I in brain and risk of Alzheimer�s
disease. Lancet 1997;349(9047):241-244.
3. Linder MW, Prough RA, Valdes R. Pharmacogenetics: a laboratory
tool for optimizing therapeutic efficacy. Clin Chem
1997;43(2):254-266.
4. Drug induced Parkinsonism in the aged. Parkinson�s Disease
Update 1995;50:285-286.
5. Clough CG. Parkinson�s disease management. Lancet
1991;337(8753):1324-1327.
6. Cohen G. The brain on fire? Ann Neurol 1994;36(3):333-334.
7. Rook GA, Zumla A. Gulf war syndrome: Is it due to a systemic
shift in cytokine balance toward a Th2 profile? Lancet
1997;349(9068):1831-1833.
8. Pall ML. Elevated sustained peroxynitrite levels as the cause
of chronic fatigue syndrome. Med Hypotheses. In press 1998.
Introduction
As the Decade of the Brain draws to a
close, a dramatic and fortuitous shift in our approach to the
understanding and treatment of a variety of neurodegenerative
conditions is occurring. For the past century, we have been
burdened by simplistic cause-and-effect deterministic models of
disease causality from the Newtonian germ theory schools of
Pasteur and Koch.
Perhaps because of the profound social and
economic burden of the neurodegenerative diseases on modern
society, and with the prospect of an even greater impact in future
decades, researchers world-wide are pursuing what at first glance
may appear to be unrelated avenues of research in hopes of gaining
a fuller understanding as to a unified theory underlying the
neurodegenerative conditions. The small puzzle pieces provided by
the multitude of researchers now seem to be crystallizing into a
recognizable and useful model unified by a broad base of seemingly
disparate etiologic factors including infectious agents, genetic
predisposition, environmental factors, endotoxic factors,
metabolic abnormalities, traumatic events, electromagnetic
radiation exposure, antioxidants, sex hormones, pharmaceutical
drugs, and others.
The cornerstone of this emerging model seems
to focus on the critically important role of mitochondrial energy
metabolism and its relationship to the toxic effects of excitatory
neurotransmitters . In this model, excitatory neurotransmitters
(predominantly glutamate) stimulate specific neuronal receptors
which, when altered by deficient mitochondrial ATP production,
leads to a self-perpetuating cascade of events ultimately
culminating in neuronal death.
This monograph will explore the
�excitotoxic� theory of neurodegenerative diseases by providing a
broad overview of the mechanisms involved ultimately leading to
cell death, as well as specific and exciting therapeutic
interventions based upon this model which are now demonstrating
efficacy.
Mitochondrial Dysfunction
The direct clinical consequences of
mitochondrial dysfunction in specific diseases have long been
appreciated. The clinical manifestation of specific types of
mitochondrial pathology are well understood in such syndromes as
Kearn-Sayre syndrome (KSS), Leber�s hereditary optic neuropathy (LHON),
mitochondrial myopathy, encephalopathy, lactic acidosis, and
strokelike episodes (MELAS), chronic progressive external
ophthalmoplegia (CPEO), Luft�s disease, and others. In these
diseases, specific mitochondrial DNA abnormalities and consequent
abnormalities of the mitochondrial respiratory chain activity have
been well delineated. It is now recognized, however, that
acquired mitochondrial DNA abnormalities can also set the
stage for significant clinical manifestations. Oxidative damage to
mitochondrial DNA has been estimated to be 10-fold higher than
damage to nuclear DNA.1 It has been estimated that
mitochondrial DNA mutation rate may be 17 times higher compared to
nuclear DNA.2 These findings are not surprising in that
mitochondrial DNA is located in close proximity to the inner
mitochondrial membrane which is the site of greatest cellular
production of reactive oxygen species (ROS). Further, unlike
nuclear DNA, mitochondrial DNA lack significant DNA repair
mechanisms.3
It is now known that several important
neurodegenerative conditions are characterized by defects of
mitochondrial function. In Parkinson�s disease, it has been
estimated that there is a 35% deficiency of complex I in the
substantia nigra.4 Deficiencies of cytochrome oxidase
(complex IV) activity in the cerebral cortex as well as platelets
of Alzheimer�s disease have been reported.5
The importance of decreased efficiency of
mitochondrial oxidative phosphorylation activity is
multi-factorial. Perhaps the most important consequence of
inefficient energy production is a change in the neuronal
transmembrane potential. Under normal conditions, with adequate
mitochondrial energy production, a normal trans-membrane potential
exists. The transmembrane potential has a profound effect on the
activity of a specific receptor for the excitatory
neurotransmitter glutamate. This receptor (NMDA receptor) under
normal conditions of transmembrane electrochemical gradient
(normal mitochondrial ATP production) is functionally blocked by
magnesium ion. When mitochondrial oxidative phosphorylation
activity becomes depressed, alterations in the transmembrane
potential relieve the magnesium block of the NMDA receptor which,
when stimulated by the excitatory neurotransmitter glutamate,
causes influx of calcium into the cytosol.
It is the influx of calcium into the cell
which plays a pivotal role in the cascade of events leading to
neuronal destruction including activation of nitric oxide synthase,
increased mitochondrial free-radical production, and activation of
proteases and lipases.
It is interesting to note that in
Parkinson�s disease, Huntington�s disease, and Alzheimer�s
disease, mitochondrial dysfunction leading to excessive
free-radical production and oxidative tissue damage seems to be
confined to the brain despite the fact that the underlying
mitochondrial abnormality is systemic. Indeed,
mitochondrial defects in platelets in Parkinson�s disease (50%
deficiency in complex I activity) have been well described.6
This may be explained by the unique susceptibility of the brain to
mitochondrial dysfunction and resultant excessive free-radical
production since the brain uses approximately 20% of the total O2
consumption (while representing only 1/50th of the body weight).
Thus, being so highly metabolic, brain tissue generates more
oxyradicals. Second, neurons are post-mitotic. This allows
accumulation of oxidatively damaged DNA, proteins, and lipids
compared to cells which retain the property to undergo mitosis.
Third, compared to other highly metabolic tissues, the brain has
relatively low levels of protectant antioxidant enzymes and
small-molecule antioxidants.7
It has long been known that there is a
significant relationship between previous xenobiotic exposure and
the risk of various neurodegenerative diseases including
Alzheimer�s disease, Parkinson�s disease, and amyotrophic lateral
sclerosis. As reported by Semchuk in 1992, �Consistently having a
history of occupational herbicide use resulted in a significant
increased Parkinson�s disease risk of about three fold �.�8
If indeed mitochondrial dysfunction plays an
important role in the pathogenesis of neurodegenerative diseases
and the various studies indicating increased risk with xenobiotic
exposure are valid, what mechanism could relate these two
concepts? The answer to this question may have been provided in a
report by Davis et al. in 1979.9 This report described
the production of a Parkinsonian syndrome in humans exposed to
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyradine), an analog of
Meperidine. It was subsequently found that MPTP administered to
various animals, predominantly primates, would likewise produce a
syndrome mimicking human Parkinson�s disease. Further, animals
treated in this manner were found to be responsive to typical
anti-Parkinsonian medications. The discovery of MPTP provided
valuable information, which has a direct bearing on the
understanding of the etiology of Parkinson�s disease. First, it
has been discovered that MPTP is a specific direct inhibitor of
complex I of the electron transport chain.10 Inhibition
of complex I causes depletion of ATP production, altering the
neuronal trans-membrane gradient rendering the NMDA receptor more
receptive to glutamate. The resulting influx of calcium enhances
reactive oxygen species generation which further damages
mitochondrial activity in a self-propagating feed-forward cycle,
ultimately leading to cell death. The importance of NMDA receptor
sensitivity as a link in this destructive chain is exemplified by
the work of Tursky who demonstrated that blocking the NMDA
receptor with specific antagonists would prevent damage to the
substantia nigra in experimental animals exposed to MPTP.11
Further, it appears that nitric oxide plays a pivotal role in the
toxicity to substantia nigra neurons induced by MPTP. Mice
pre-treated with 7-nitroindazole, a nitric oxide synthase
inhibitor, demonstrate a dose-dependent protection against MPTP
substantia nigra damage.12 This implies that nitric
oxide formation also plays an important role with respect to
free-radical neuronal damage induced by mitochondrial energy
production dysfunction. Clarification of the mechanism of neuronal
injury whereby MPTP is metabolized to reactive MPP+, which is then
selectively transported across the neuronal membrane by specific
dopamine transporters leading to mitochondrial damage, has
encouraged researchers to identify other exogenous or endogenous
chemicals which may act in a similar fashion.
Recently, Dr. Manfred Gerlach published
research identifying N-methyl-(R)-salsolinol as a possible
endogenous MPTP-like neuro-toxin.13 The possibility
that xenobiotics may act in a fashion similar to MPTP, coupled
with the obvious link of Parkinson�s disease risk with pesticide
exposure, has encouraged research specifically focused on the role
of xenobiotics as toxic agents with respect to mitochondrial
function. In a study reported by Flemming et al., Dieldrin, a
lipid-soluble long-lasting mitochondrial toxic pesticide, was
found in six of twenty brains of Parkinson�s patients and in none
of controls.14
But what appears as perhaps an obvious
question with respect to the increased risk of Parkinson�s in
individuals exposed to pesticides is why some of those exposed
will manifest the disease while most will not. Could some
individuals manifest dysfunction of xenobiotic metabolism to the
extent that toxic metabolites are not cleared appropriately and
thus remain within the body, ultimately inflicting damage on
delicate neuronal homeostatic mechanisms? The answer to this
question has perhaps best been answered by Steventon and others
who have demonstrated significant abnormalities of xenobiotic
metabolism in Alzheimer�s disease, Parkinson�s disease, motor
neuron disease, and even rheumatoid arthritis.15,16 The
specific abnormalities of detoxification described by these
authors involve decreased activity of phase II sulfation. Phase I
abnormalities including the P450 enzymes IID6 and cysteine
dioxygenase have also been described.17 Identification
of �at risk� individuals, i.e., those individuals with inherited
hepatic detoxification flaws, may allow the development of
preventive strategies to reduce the likelihood of disease
manifestation. Specific evaluation of hepatic detoxification
pathways is now widely available.18
The NMDA
Receptor
In recognizing the importance of the NMDA
receptor in the cascade ultimately leading to neuronal death,
various schemes have been proposed to block the glutamate
stimulation of this receptor. It has long been recognized that
patients treated with Amantadine for Parkinson�s disease survived
longer compared to those who did not receive this medication. The
specific mechanism by which Amantadine may be helpful in this
regard may stem from its �neuro-protective� effect mediated
through the antagonism of the NMDA receptor.19
Inhibiting glutamate stimulation of the NMDA receptor is the
proposed mechanism by which gabapentin and riluzole have purported
efficacy in motor neuron disease. The use of branched chain amino
acids (L-leucine, L-isoleucine, and L-valine) in amyotrophic
lateral sclerosis, although not having been shown to be
significantly effective, was proposed as this group of amino acids
is known to inhibit glutamate production. Further, excessive
glutamate as a consequence of deficient clearance from the
synaptic cleft may represent a specific mechanism for excessive
NMDA receptor stimulation in amyotrophic lateral sclerosis.20
Nitric
Oxide
As described above, nitric oxide (NO) seems
to play a pivotal role in the cascade of events leading to
neuronal death following glutamate stimulation of the NMDA
receptor. Nitric oxide is formed when L-arginine is oxidized to
citrulline by the action of the enzyme nitric oxide synthase.
Although nitric oxide itself is a free radical due to its unpaired
electron, it is not felt to participate in any significantly
damaging chemical reactions in and of itself. However, when
reacting with superoxide anion, the extremely reactant and potent
oxidant peroxynitrite (ONOO) is formed. This reaction is
approximately three times faster than the reaction dismutating
superoxide to form hydrogen peroxide catalyzed by superoxide
dismutase (SOD).21 Peroxynitrite has been implicated in
a variety of damaging intra-neuronal events including DNA strand
breaks, DNA deamination, nitration of proteins including
superoxide dismutase, damage to mitochondrial complex I, complex
II, and mitochondrial aconitase. In addition, nitric oxide itself
also specifically damages mitochondrial complex I.22
Thus, nitric oxide physiology has been a
central focus of research in the neurodegenerative diseases.
Inhibiting its synthesis may provide an avenue for reducing the
neuro-destructive capabilities of extrinsic toxins which may have
implications in the neurodegenerative disorders, if in fact
extrinsic toxins (or even endogenously produced toxins)
participate in chronic expression of nitric oxide synthase. The
role of nitric oxide in the pathogenesis of Parkinson�s disease is
exciting and remains the focus of vigorous research. Hantraye and
associates in Orsay, France published research in 1996
demonstrating that pre-treatment of baboons with the nitric oxide
synthase inhibitor 7-nitroindazole (7-NI) completely prevented the
induction of Parkinsonism in baboons exposed to MPTP. These
researchers demonstrated that inhibiting nitric oxide synthase
�protected against profound striatal dopamine depletion and loss
of tyrosine hydroxylase-positive neurons in the substantia nigra�
and �protected against MPTP-induced motor and frontal-type
cognitive deficits.�23
Elevated levels of nitric oxide synthase
have been found in the brains of patients with multiple sclerosis.
Bagasra and colleagues at Thomas Jefferson University demonstrated
elevated levels of nitric oxide synthase messenger RNA in 100% of
the CNS tissues from seven multiple sclerosis patients, but in
none of three normal brains. The authors conclude, �These results
demonstrate that NOS, one of the enzymes responsible for the
production of nitric oxide, is expressed at significant levels in
the brains of patients with MS and may contribute to the pathology
associated with the disease.�24
Nitric oxide may also play an important role
in the pathogenesis of Alzheimer�s disease. Beta-amyloid plaques
are a characteristic histopathological finding in Alzheimer�s
disease. When cultured rat microglia are exposed to beta-amyloid,
there is a prominent microglial release of nitric oxide especially
in the presence of gamma- interferon.25 In cortical
neuronal cultures, treatment with nitric oxide synthase inhibitors
provides neuro-protection against toxicity elicited by human
beta-amyloid.26
The role of nitric oxide in mediating
neuronal damage in cerebral ischemia is also the subject of
intense research. Again, the operative model recognizes excessive
glutamate stimulation of the NMDA receptor in cerebral ischemia
with elevation of intracellular calcium and induction of nitric
oxide synthase raising intra-neuronal nitric oxide. In addition,
elevated cytosolic calcium converts the enzyme xanthine
dehydrogenase to xanthine oxidase which results in excessive
superoxide anion formation, thus setting the stage for the
production of the highly reactive peroxy-nitrite radical (ONOO-)
via the mechanism described above. Transgenic mice over-expressing
SOD with resultant decreased superoxide formation are protected
against focal ischemia, as are mice which genetically lack nitric
oxide synthase.27
Because of the wide-ranging implications of
nitric oxide chemistry in both acute and chronic neuro-destructive
entities, selected inhibition of nitric oxide synthase has become
the focus of extensive pharmaceutical research. Specific attempts
to inhibit nitric oxide synthase include the use of arginine
analogues, which compete with L-arginine for catalytic binding
sites on nitric oxide synthase. Arginine analogues, however, are
associated with profound cerebral vaso-constriction and thus may
result in worsening perfusion.28
Nutritional approaches focusing on increased
dietary citrulline may offer an alternative approach to reducing
nitric oxide formation. As noted by Larrick, �Although citrulline
is not one of the amino acid building blocks of protein, large
quantities of free citrulline do occur in some foods such as
watermelon, Citrullus vulgaris, which contains 100 mg/100
grams.�29
Substituted guanidoamines may demonstrate
therapeutic promise through the mechanism of inhibition of nitric
oxide synthase, especially in multiple sclerosis. In auto-immune
encephalomyelitis in mice (an animal model for multiple
sclerosis), aminoguanidine, an inhibitor of nitric oxide synthase,
when administered to mice sensitized to develop experimental
auto-immune encephalomyelitis, specifically inhibited disease
expression in a dose-related manner.30
Functional
Intervention
The energy-linked excitotoxic model
described above reveals multiple targets of susceptibility whereby
compromised function can begin a progressive, feed-forward and
thus self-perpetuating cascade ultimately culminating in neuronal
death. These include excessive glutamate leading to excessive NMDA
receptor stimulation (as noted in cerebral ischemia and
amyotrophic lateral sclerosis); enhanced NMDA receptor sensitivity
to glutamate as a consequence of altered electro-chemical gradient
due to decreased mitochondrial ATP production (as noted in
idiopathic Parkinson�s disease, MPTP-induced Parkinsonism,
Huntington�s chorea, Alzheimer�s disease, and various inherited
mitochondropathies); formation of NMDA receptor antibodies
allowing persistent cellular inflow of calcium (noted in
amyotrophic lateral sclerosis); enhanced nitric oxide production
(as noted in Parkinson�s disease, Alzheimer�s disease, animal
models, multiple sclerosis animal models, and ischemic stroke);
deficiencies of small molecule antioxidants and antioxidant
enzymes (Huntington�s chorea, Alzheimer�s disease, amyotrophic
lateral sclerosis, and Parkinson�s disease); and deficiencies of
xenobiotic metabolism allowing accumulation of neuro-toxic
intermediates (amyotrophic lateral sclerosis, Alzheimer�s disease,
and Parkinson�s disease).
Inhibition
of Glutamate Release/NMDA Stimulation
A number of protective agents are thought to
act by inhibiting either the release of glutamate or the
subsequent stimulation of the NMDA receptor. These include the
anti-convulsants gabapentin, lamotrigene, diphenylhydantoin,
carbanazepine, and riluzole, a pharmaceutical agent developed for
the treatment of amyotrophic lateral sclerosis. Huperzine A, an
ancient Chinese herbal medicine (Qian Ceng Tan), was recently
described in the Journal of the American Medical Association
as a possible new therapy for Alzheimer�s disease. In addition to
having acetylcholinesterase inhibition activity, Huperzine A
specifically inhibits glutamate stimulation of the NMDA receptor.31
Mitochondrial Function
One of the most promising agents for
up-regulation of mitochondrial function is Coenzyme Q-10. Coenzyme
Q-10, in addition to having free-radical scavenging properties, is
known to play a pivotal role in transporting electrons in the
mitochondria for ATP production. The usefulness of Coenzyme Q-10
in specific mitochondrial myopathies has been well described.
Bresolin and co-workers in Milano, Italy have described enhanced
mitochondrial activity as evidenced by reduction of serum lactate
and pyruvate following standard muscle exercise with generally
improved neurologic functions in Kearns Sayre syndrome and chronic
progressive external ophthalmoplegia.32 Idebenone, a
Coenzyme Q-10 derivative with increased blood-brain barrier
penetration, produced enhanced cerebral metabolism in a
36-year-old man with MELAS (mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes) during
a five-month treatment protocol providing Idebenone up to 270 mg
per day. Cerebral metabolism in this study was followed with PET
(positron emission tomography) studies.33
Finally, preliminary studies by Jenkins have
demonstrated lowering of cerebral lactate levels in vivo in
Huntington�s disease in a patient receiving Coenzyme Q-10 310 mg
per day. There was an average of 29% decrease in lactate levels
following treatment as demonstrated by magnetic resonance
spectroscopy.34
Phosphatidylserine enhances both neuronal
and mitochondrial stability and activity and reduces mitochondrial
free-radical production. Researchers at Stanford University School
of Medicine evaluated a group of 149 patients meeting criteria for
�age-associated memory impairment� over a period of twelve weeks
with either phosphatidylserine (100 mg t.i.d.) or placebo. Actual
improvement in the treated group on psychometric testing related
to learning and memory was seen in a majority of patients,
specifically those who had scored above the range of cognitive
performance associated with dementing disorders such as
Alzheimer�s disease, but who were performing in the low normal
range for persons of the same age. As the authors reported,
�Results of this study suggest that phosphatidylserine may be a
promising compound for the treatment of memory deficits that
frequently develop in the later decades of adulthood. Effects were
present on a number of outcome variables related to such important
tasks of daily life as learning and recalling names, faces, and
numbers. Drug effects may also generalize to other difficult tasks
involving learning, memory, and concentration since improvement
was also present on a standard neuro-psychological test that
measures the ability to remember details of a story after it is
read. This finding may be related to the common complaint in later
adulthood of difficulty in remembering what one just read in a
newspaper, book, or magazine article.�35 Similar
results have been noted in other studies.36,37
Monoamine oxidase type B (MAO-B) catalyzes
the oxidation of dopamine to dihydroxyphenylacetaldehyde with
formation of hydrogen peroxide. In the absence of adequate
glutathione peroxidase (well described in Parkinson�s disease),
excessive hydrogen peroxide is available to participate in the
Fenton reaction whereby hydrogen peroxide combines with ferrous
iron forming ferric iron and the highly reactive hydroxyl radical.
Thus, inhibition of MAO-B may offer therapeutic benefit in
Parkinson�s disease and in other neurodegenerative conditions
characterized by free-radical production as a consequence of
oxidation of cerebral catecholamines. Selegeline, a potent
inhibitor of MAO-B, having long been demonstrated to delay the
need for dopamine-replacement therapy in Parkinson�s disease, is
now being evaluated for its ability to improve cognitive defects
associated with Alzheimer�s disease.38 Interestingly,
it has been demonstrated that extracts of Ginkgo biloba leaf also
have a profound inhibitory influence on MAO-B.39 In
addition, Ginkgo biloba is known to be involved in such diverse
processes as homeostasis of inflammation, reduction of oxidative
stress, membrane protection, and neuro-transmission modulation. Le
Bars and co-workers, in research recently published in the
Journal of the American Medical Association, evaluated 202
patients suffering from Alzheimer�s disease or multi-infarct
dementia over a 52-week period of time. These subjects received
either an extract of Ginkgo biloba or placebo. In the treatment
group a substantial number of patients either stabilized or
actually demonstrated improvement in cognitive performance as
measured by psychometric testing, and this was of sufficient
magnitude that it was frequently recognized by the care-giver.40
Increased intra-cellular calcium is known to
enhance the conversion of the enzyme xanthine dehydrogenase (which
metabolizes xanthine to uric acid plus NADH) to xanthine oxidase
(converts xanthine to uric acid plus superoxide radical). This
provides another mechanism whereby increased cytosolic calcium
enhances the free-radical load. Unpublished research by Dr.
Stanley Appel is evaluating the efficacy of allopurinol (a potent
inhibitor of xanthine dehydrogenase and xanthine oxidase) in
amyotrophic lateral sclerosis.41 Clearly, the enzymatic
shift favoring xanthine oxidase with its resultant increase in
superoxide formation has implications in many other
neurodegenerative entities. Since allopurinol inhibits both
xanthine dehydrogenase and xanthine oxidase, overall production of
uric acid is decreased. Uric acid may have antioxidant properties,
thus selective inhibition of xanthine oxidase would be more ideal.
Sheu and co-workers at Tai Pei Medical College have demonstrated
the specific inhibitory effect of silymarin on xanthine oxidase.42
As described above, the role of nitric oxide
in acute and chronic neurological illnesses is multi-factorial.
Dietary inhibition of nitric oxide formation by citrulline was
described above. Kong, and co-workers at the National Institute of
Environmental Health Sciences have demonstrated that glial cell
cultures stimulated to produce nitric oxide by a combination of
lipopolysaccharide and interferon-gamma are significantly
inhibited with respect to nitric oxide production when treated
with genistein.43
Acetyl-L-carnitine has been demonstrated to
specifically increase cellular ATP production. It was shown to
prevent MPTP-induced neuronal injury in rats.44
Further, Acetyl-L-carnitine reduces production of mitochondrial
free-radicals, helps maintain transmembrane mitochondrial
potential, and enhances NAD/NADH electron transfer.45
Thal and colleagues at the University of California San Diego
evaluated the efficacy of Acetyl-L-carnitine, 1 gram t.i.d. for
twelve months in a multi-center, placebo-controlled study of 431
patients with Alzheimer�s disease, 83% of whom completed the one
year study. Their results demonstrated ��a trend for early-onset
patients on Acetyl-L-carnitine to decline more slowly than
early-onset Alzheimer�s disease patients on placebo.�46
Alpha lipoic acid is emerging as one of the
most promising agents for neuro-protection in neurodegenerative
diseases. This potent antioxidant demonstrates excellent
blood-brain barrier penetration. It acts as a metal chelator for
ferrous iron, copper, and cadmium, and also participates in the
regeneration of endogenous antioxidants including vitamins E, C,
and glutathione. Although no large clinical evaluation of the
usefulness of alpha lipoic acid in neurodegenerative diseases has
as yet been published, an excellent review in a paper entitled
�Neuro-protection by the metabolic antioxidant alpha lipoic acid�
by Packer and co-workers in Frankfort, Germany provides enough
justification for strong consideration of alpha lipoic acid as a
neuro-protectant for neurodegenerative conditions.47
The lipophilic antioxidant vitamin E is
thought to play a major role in defending mitochondria against
oxidative stress. Since mitochondrial ATP production is a
membrane-bound event, reducing oxidative membrane damage would
likely slow the decline of oxidative phosphorylation potential.48
In a report published in the New England Journal of Medicine,
researchers at Columbia University College of Physicians and
Surgeons studied 341 patients with Alzheimer�s disease of moderate
severity receiving selegeline 10 mg per day, alpha-tocopherol
(vitamin E) 2000 i.u. a day, both, or placebo, over a two-year
period of time. The results revealed that the primary outcomes of
death, institutionalization, loss of the ability to perform basic
activities of daily living, or severe dementia were prolonged in
the groups receiving selegeline or vitamin E compared to the
groups receiving placebo or selegeline and vitamin E.49
Melatonin, in addition to having
free-radical scavenging properties,50 has also been
demonstrated to increase gene expression for antioxidant enzymes.
Kotler has demonstrated increased levels of mRNA for glutathione
peroxidase, copper-zinc superoxide dismutase, and manganese
superoxide dismutase in melatonin-treated rat brain cortex.51
These properties in addition to the ability of melatonin to
readily traverse the blood-brain barrier as well as its lipid and
aqueous solubility provide substantiation for consideration of
melatonin in neurodegenerative conditions.
Glutathione is an important cerebral
mitochondrial antioxidant maintaining both vitamin E and vitamin C
in their reduced state and removing potentially damaging
peroxides. A profound decrease in brain glutathione has been
demonstrated in Parkinson�s disease.52 Intravenous
reduced glutathione has been used as a treatment of early
Parkinson�s disease. Sechi administered reduced glutathione 600 mg
twice daily for thirty days in an open label study on patients
with early Parkinson�s disease. All patients improved
�significantly� after glutathione therapy, with a 42% decline in
disability. The therapeutic effect lasted for 2-4 months after
therapy. They concluded, �Our data indicate that in untreated
Parkinson�s disease patients, glutathione has symptomatic efficacy
and possibly retards the progression of the disease.�53
The nutritional supplement N-acetyl-L-cysteine
has been demonstrated to increase intra-cellular cysteine levels,
enhancing glutathione production.54 In addition,
glutathione may be enhanced by the use of alpha lipoic acid (see
above), L-cysteine, L-methionine, L-glutamine, reducing xenobiotic
challenges, reducing drug challenges which induce cytochrome P450
enzymes, complementary antioxidants including vitamins C and E,
and silymarin, which acts by increasing glutathione retention.
Finally, it is noted that N-acetyl-cysteine may act as a potent
antioxidant in that it inhibits the production of nitric oxide.55
NADH plays a pivotal role in the function of complex I of the
respiratory chain. Enzyme function of NADH ubiquinone reductase in
the platelets of Parkinson�s disease patients is noted to be
30-60% lower than that of aged match controls. This activity
increases following administration of NADH. Birkmayer has
demonstrated improvements of short-term memory and other cognitive
functions in Parkinson�s patients treated with NADH. He felt that
NADH would prove helpful in Parkinson�s disease since NADH
stimulates tyrosine hydroxylase, the rate-limiting enzyme for
dopamine biosynthesis. Because deficiencies of dopamine and
noradrenalin are found in patients with senile dementia of the
Alzheimer�s type, he studied the usefulness of NADH in 17 patients
suffering from dementia of the Alzheimer�s type in an open label
trial. Using the mini-mental status examination, he found that all
17 patients treated with NADH, 5 mg twice a day, improved. Minimum
improvement was 6 points with a maximum of 14 and a mean of 8.35
points with therapy ranging from 8 to 12 weeks.56
Conclusion
Over the next several decades, Alzheimer�s
disease, Parkinson�s disease, amyotrophic lateral sclerosis,
multiple sclerosis, and other neurodegenerative diseases will have
an ever increasing impact on our society emotionally, socially,
and financially. While at first glance unraveling the complex
mechanisms involved in the pathogenesis of these seemingly
discrete clinical entities may seem daunting, modern research
clearly reveals that these seemingly unique clinical entities are
simply variations on a theme.
With this understanding, meaningful
functional interventions based upon high caliber scientific
research are justified.
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David Perlmutter, M.D., is a board-certified
neurologist who practices neurology and preventive medicine. One
of the leading authorities in the field of adult and pediatric
neurology, he is founder and director of the Perlmutter Health
Center in Naples, Florida. He has been a pioneer in the
application of functional medicine concepts and the use of
functional assessments in the treatment of neurological disease.
David Perlmutter, M.D.
Diplomate American
Board of Psychiatry and Neurology
800 Goodlette Rd., Suite 270
Naples, FL 34102
Tel: 941-649-7400
Fax: 941-649-6370
www.perlhealth.com
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