Reprinted from Townsend Letter for Doctors & Patients, January, 1997

Parkinson's Disease - New Perspectives

by David Perlmutter, M.D.

James Parkinson in his "Essay on Shaking Palsy" described his observations of six patients having virtually all of the typical clinical features of the now widely recognized disorder that bears his name. Earlier descriptions of Parkinson's disease date back to the work of Leonardo DaVinci, and perhaps even as far back as early Egyptian and Hindu writings. During the first 140 years after Parkinson's' Essay, precious little progress was made in either understanding the pathophysiology of the illness or in developing any form of effective treatment.

In 1960, Ehringer and Hornykiewicz demonstrated that the basal ganglia in Parkinson's disease patients were profoundly deficient in the neurotransmitter dopamine. The deficiency of dopamine from the basal ganglia of Parkinson's patients was correlated directly with loss of cells in the substantia nigra. Early efforts aimed at utilizing dopamine were uniformly unsuccessful because dopamine is unable to traverse the blood-brain barrier. Levodopa, being able to penetrate the blood-brain barrier and serving as a precursor for dopamine, gained early recognition in the treatment of this disease and continues to serve as the mainstay of treatment. But as Moore recently reported in the New England Journal of Medicine, "Nevertheless, it is now clear the levodopa and the receptor agonists are only limited ameliorative treatments, and that the course of most patients is one of inexorably progressive disability regardless of therapy. Furthermore, the treatment is usually associated with a series of unpleasant and distressing side effects, including drug induced dyskinesias, ‘on and off' phenomena, and psychiatric disturbances."

Recent advancements in microneurosurgical stereotactic technique have led to the development of various ablative procedures including tractotomy and palidotomy as well as implantation techniques involving autograft of adrenal medulla to the caudate nucleus, have met with limited success, but will doubtfully gain widespread application due to their invasiveness and overwhelming expense.

Until now, the main emphasis in the development of treatment strategies for Parkinson's disease has focused upon strategies to reestablish basal ganglionic dopamine or to inhibit neurotransmittors whose activity becomes enhanced by dopamine's deficiency. Little attention has been paid to gaining an understanding of the fundamental cause of Parkinson's disease, i.e. the progressive degeneration of the dopamine producing cells of the substantia nigra. ⁷

In 1991, Jenner described post mortem studies in which there was evidence in the substantia nigra for an on-going toxic process involving increased lipid peroxidation, as well as altered iron metabolism, leading to increased iron concentration in the substantia nigra. He felt that this evidence implicated oxidative stress as an important factor contributing to neuronal loss. Oxidative stress as a consequence of free radical production is enhanced in the presence of free (unbound) iron which serves as a catalyst in the conversion of hydrogen peroxide (produced as a byproduct of the oxidative deamination of dopamine) to the highly reactive hydroxyl radical. ⁹ Further, Jenner felt that increased iron levels likely did not initiate Parkinson's disease, but rather acted to accelerate cell death. Iron-catalyzed free radical generation has also been described by Mash as a cause of substantia nigra cell destruction in Parkinson's disease. He hypothesized that defects in iron handling by the transferrin receptor may contribute to the formation of free radical species which catalyze lipid peroxidation of substantia nigra cell membranes.

Recent evidence supports another iron-binding protein, lactoferrin as playing an important role in the excessive accumulation of iron in the substantia nigra of Parkinson's disease patients. His research has demonstrated an over expression of the lactoferrin receptor when utilizing immunohistochemical staining techniques to evaluate the dopaminergic areas of the brains of patients who had died with Parkinson's disease.

Faucheux hypothesizes that over expression of the lactoferrin receptor and consequent excessive deposition of iron may be due to a defect of an intracellular feedback loop.⁹ In a recent editorial appearing in The Lancet, Dorothy Bonn summarized the implications of this exciting research by stating, "The question now is whether lactoferrin participates only in the binding, transport, and accumulation of iron, or whether by chelating iron within the cell it might actually be involved in neruonal protection." ⁹

The chelating agent ethylene-diamine-tetra-acetate (EDTA) has an extremely high affinity for unbound iron. According to Cranton, "EDTA can reduce the production of free radicals by a million-fold. It is not possible for the free radical pathology to be catalytically accelerated by metallic ions in the presence of EDTA. Traces of unbound metallic ions are necessary for uncontrolled proliferation of free radicals in living tissue. EDTA binds ionic metal catalysts, making them chemically inert and removing them from the body.

The hypothesis that oxidative destruction of cells of the substantia nigra may be in part responsible for the progression of Parkinson's disease has led researchers to explore the usefulness of antioxidants in slowing the progression of the disease. Fahn in an open-labeled trial, found that the time when levodopa became necessary was extended by 2.5 years in a group of patients with Parkinson's disease taking high dose antioxidants. These patients ultimately received vitamin E 3,200 I.U. and vitamin C 3,000 mg on a daily basis in four divided doses.

Among the most important events helping to unravel the mystery of Parkinson's disease occurred in 1982, when seven heroin addicts developed Parkinson's disease after they injected a preparation of synthetic Meperidine 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). Shortly thereafter, exposure to MPTP was found to produce Parkinson's disease in a variety of primate species in which an accompanying loss of cells in the substantia nigra was also demonstrated. Interestingly, the neurotoxic effects induced by MPTP can be prevented in mice when treated with an extract of the Chinese herb Gingko biloba. As the MPTP story evolved, the concept that some environmental factor could play a role in the genesis of Parkinson's disease gained popularity. Attention was directed to man-made (xenobiotic) chemicals to determine if there were any similarities to MPTP Paraquat, a formerly widely used herbicide with a chemical structure quite similar to MPTP was heavily scrutinized as a candidate for causing Parkinson's disease. Research failed to incriminate Paraquat as an etiologic agent. But despite the fact that Paraquat was not implicated, researchers have continued to explore other environmental agents which may play a role in this disease. Epidemiologic studies have demonstrated a clear relationship between various agricultural chemicals and risk for development of Parkinson's disease. Barbeau found a very high correlation between Parkinson's disease and the use of pesticides. In comparing one farming area southwest of Montreal where pesticides were used in large amounts to areas in the same region with low pesticide use, the incidence of Parkinson's disease was seven times greater in the former. Goldsmith has reported an extremely high incidence of Parkinson's disease on three adjacent kibbutzim in the Negev region of Israel whose water has been supplied from wells draining a common aquifer. The incidence of Parkinson's disease was reported to be five times greater in each of the three kibbutzim than in the remainder of the region. A history of occupational herbicide use has been described as significantly increasing risk of Parkinson's disease by about three fold with data also suggesting a dose-response relation between the duration of cumulative lifetime exposure to agricultural work and risk of Parkinson's disease.

With these observations, the central question which arises must attempt to explain the uniqueness of the individual allowing the progression of Parkinson's disease in the face of exposure to xenobiotic chemicals, and further relate this predisposition to enhanced oxidative destruction of the dopamine producing substantia nigra cells.

The possible relationship between a genetic predisposition and an environmental exposure was well summarized by Seidler when he stated, "Although there is increasing evidence that genetic factors may also play a role in the etiology of Parkinson's disease, at least in some patients, this likely involves interaction with environmental factors. For example, defects in enzyme detoxification systems --- could lead to potentiation of relatively low-level neurotoxic exposures in Parkinson's disease patients. Such environmental-genetic interaction is supported by heritability coefficients for Parkinson's disease as calculated from several genetic studies ...."

Steventon demonstrated profound defects in sulfate conjugation (part of the phase II hepatic detoxification system) in a majority of Parkinsonian patients studied. Several hepatic P-450 enzymes have also been implicated in Parkinson's disease including P-450 II D6, and cystine dioxygenase. Indeed, variant alleles coding for specific cytochrome P 450 isoenzymes have been identified with increased frequency in individuals with Parkinson's disease, especially those with "early onset" type disease.

Recently, therapeutic schemes have been developed utilizing nutritional approaches in an attempt to up regulate dysfunctional hepatic enzyme systems. In 1992, Bland described a nutritional intervention program designed to improve hepatic detoxification enzyme systems. After a three week period, subjects placed on a specific dietary program augmented in nutrients identified as supportive in up-regulation of hepatic detoxification demonstrated significant improvement in caffeine clearance (a measure of hepatic cytochrome P 450 activity) as well as sodium benzoate conversion (hippurate excretion) which is a measure of glycine conjugation - an important aspect of phase II liver detoxification activity. ²³

Report of a Case: B.K. is a 40 year old male who, in 1989 at the age of 34, began experiencing a tremor of the right hand. This was associated with micrographia and subsequently a right lower extremity tremor as well. Over the next several years he developed bradykinesia, masking of the faces, and loss of associated arm movements with ambulation. He was placed on a sustained release preparation of carbidopa-levodopa which produced a significant improvement of his symptoms. When evaluated on 10/10/95, his medications included sustained release carbidopa-levodopa (Sinimet CRÔ 25/100) three times each day, carbidopa-levodopa (Sinimet 25/100) twice each day, Selegiline (Eldepryl Ô) 5 mg twice each day, and Bromocriptine Mesylate (ParlodelÔ ) 5 mg twice a day. His past medical history was negative for head trauma, manganese exposure, carbon monoxide exposure, but he did report having lived directly adjacent to a large commercial pesticide-using farm for the first twelve years of his life.

On 02/06/96, the patient began a two week nutritional program utilizing a diet and nutritional supplement based upon Bland's program for hepatic enzyme up-regulation (see above). This program utilized 44 grams of UltraClear PlusÔ ^A twice a day.

After completing the two week program, the patient reported, "My medications are working better." He was experiencing increased energy, and there was a marked reduction of tremor on physical examination. Video tapes were made prior to and subsequent to the treatment protocol, and a significant improvement was also noted in fluidity of movement, facial expression, and associated arm movements with ambulation. In addition, the patient was able to substantially reduce his levodopa dosage by completely eliminating two tablets of carbidopa-levodopa 25/100 from his daily regimen.

The patient remains on 44 grams of UltraClear PlusÔ each day. Four months after the original nutritional intervention, his improvement persists, and he has not had to increase his levodopa regimen.

Functional assessment of both phase I cytochrome P 450 as well as phase II hepatic detoxification competence is now easily determined. Great Smokies Diagnostic Laboratory^B provides a Detoxification Profile utilizing caffeine, acetaminophen, and salicyclic acid. This study provides comprehensive results characterizing adequacy of phase I cytochrome P 450 activity as well as Phase II functions including glutathione conjugation, sulfation, glucuronidation, and glycine conjugation. Free radical markers are also assessed. We utilize this Profile to determine which of our Parkinson's disease patients would most likely benefit from a hepatic enzyme up-regulation protocol. It has been our experience that those patients who benefit most from this protocol are "early onset," typically having onset of symptoms before age 50 years.

Unbound iron clearly plays an important role in the free radical mediated damage of dopamine producing cells of these substantia nigra. Because EDTA has such a strong affinity for unbound iron, we routinely utilize a program of EDTA chelation therapy in the treatment of our Parkinson's disease patients.

In experimental animals, Gingko biloba extract has been demonstrated to protect the brain against the damaging effects of the Parkinson's inducing chemical MPTP. We feel Gingko biloba therefore has a useful role in our patients.

Summary: Our therapeutic protocol for Parkinson's disease patients includes:

1. Assessment of hepatic detoxification competence (Great Smokies Diagnostic Laboratory - Detoxification Profile).

2. UltraClear Plus Ô - 88 grams per day for two weeks followed by 44 grams each day (especially for patients with demonstrated abnormalities of hepatic detoxification or age of onset of symptoms less than 50 years).

3. Gingo biloba extract 60 mg twice each day.

4. EDTA Chelation therapy.

5. Vitamin C - 4000mg per day.

6. Vitamin E ( d-alpha tocopherol ) 800 units per day.

Conclusion: New and exciting research now demonstrates that the etiology of Parkinson's disease, although not clearly defined, quite likely involves an environmentally induced manifestation of a genetic predisposition. Thus, individuals with specific genetic defects causing hepatic detoxification enzyme dysfunction may develop Parkinson's disease as a result of exposure to certain environmental xenobiotic chemicals proving neurotoxic. We hypothesize that defects in fully detoxifying xenobiotics may allow damage to specific carrier systems for iron allowing increased concentration of unbound iron in the substantia nigra leading to enhanced free radical damage to dopamine producing cells.

A. UltraClear PlusÔ manufactured by HealthComm International Inc.,

P.O. Box 1729, 5800 Soundview Drive, Building B., Gig Harbor, WA 98335.

Tel. (800) 648-5883.

B. Great Smokies Diagnostic Laboratory,

63 Zillicoa St., Asheville, NC 28801-1074.

Tel. (800) 522-4762.

1. REFERENCES

1. Parkinson, J.: An Essay on the Shaking Palsy. London, Sherwood, Neely, & Jones, 1817.
2. Calne, et al: Did Leonardo Describe Parkinson's Disease? N. Engl. J. Med. 1989; 320:594.
3. Stern, G.M.: Did Parkinsonism Occur Before 1817? J. Neurol. Neurosurg. Psychiatry (Supplement) 1989; 11.
4. Ehringer, H., Hornykiewicz. Verteilung von noradrenalin und Dopamin (3-hydroxy tryptamin) im Gehrin des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin Wochenscher, 1960; 38:1236-9.
5. Moore, R.Y. Parkinson's Disease - A New Therapy? N. Engl. J. Med. 1987;316:872-3.
6. Madrazo, I., et al., Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson's disease. N. Engl. J. Med. 1987; 316:831-4.
7. Jenner, P. Oxidative stress as a cause of Parkinson's Disease. Acta Neurol Scand Suppl. 1991; 136:6-15.
8. Mash, D.C., Distribution and number of transferrin receptors in Parkinson's disease and in MPT- treated mice. Exp. Neurol. 1991; 114:73-81.
9. Bonn, D., Pumping iron in Parkinson's Disease, The Lancet 1996; 347:1614.
10. Cranton, E.M., and Frackelton, J.P., Free radical pathology in age-associated disease: Treatment with EDTA chelation, nutrition, and antioxidants in a textbook on EDTA chelation therapy, 1989; Human Sciences Press, New York, New York.
11. Fahn, S., An open trial of high-dosage antioxidants in early Parkinson's disease. Am. J. Clin. Nutri. 1991;53:380-S-2S.
12. Ballard, T.A., et al. Permanent human Parkinsonism due to Meperidine 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP): Seven cases. Neurology 1985; 35:949-956.
13. Burns, R.S., et al. A primate model of Parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by Meperidine 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). Proc. Natl. Acad. Sci. USA. 1983; 80:4546-4550.
14. Ramassamy, C., et al. In Vivo Gingko biloba extract (EG b761) Protects against neurotoxic effects induced by MPTP: Investigations into its mechanism (S) of action. In Effects of Gingko biloba extract (EG b761) on the Central Nervous System, Y. Christin, 1992; Elsevier Press, Paris.
15. Hefti, F.F. The future of Parkinson research. Parkinson Report. National Parkinson Fou.ndation, Inc., 1987; Vol. VII, - X1V.
16. Barbeau, A. Lecture at Eighth International Symposium on Parkinson's disease, New York, June, 1985.
17. Goldsmith, J.R. et al., Clustering of Parkinson's disease points to environmental etiology, Arch. Environ. Health 1990; 45:88-94.
18. Semchuk, K.M., et al., Parkinson's disease and exposure to agricultural work and pesticide chemicals, Neurology, 1992; 42:1328-1335.
19. Seidler, A., Possible environmental, occupational, and other etiologic factors for Parkinson's disease: A case-control study in Germany, Neurology, 1996;46:1275-1284.
20. Steventon, et al., Xenobiotic metabolism in Parkinson's disease, Neurology, 1989; 39:883-887.
21. Tanner, C.M., Liver enzyme abnormalities in Parkinson's disease, Geriatrics, 1991; 46 Supplement 1:60-63.
22. Agundez, J.A., et al., Association between the oxidative polymorphism and early onset of Parkinson's disease, Clin. Parmacol. Ther. 1995; 57:291-298.
23. Bland, J.S., and Bralley, J.A., Nutritional up-regulation of hepatic detoxification enzymes, Journal of Applied Nutrition, 1992; 44:3-15.