Preventive Medicine and Nutrition
Functional Therapeutics in Neurodegenerative Disease
David Perlmutter, M.D.
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., Reglanä).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.
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.
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 O2consumption (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.13The 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.17Identification 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
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
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
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.32Idebenone, 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 theNew 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.52Intravenous 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
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