From The May 2001 Issue of Nutrition Science News
Although no cures exist for this debilitating condition, long-term antioxidant intake may offer a protective benefit
By Carmia Borek, Ph.D.
Parkinson's disease (PD) is an age-related neurodegenerative disorder that affects approximately 1 million Americans. Some 60,000 cases are diagnosed each year. The average age of a Parkinson's patient is 60 years, and the disease seems to affect men and women equally. 
Named after the London physician who first described the condition in 1817, Parkinson's disease is characterized primarily by degeneration of dopamine-producing neurons in a small area of cells in the midbrain known as the substantia nigra, which results in decreased dopamine availability. Dopamine is a neurotransmitter that relays messages to the corpus striatum area to produce controlled and purposeful muscle activity. Dopamine-producing neurons project throughout the brain's cerebral hemisphere so that dopamine loss, the hallmark of PD, becomes widespread. However, the motor symptoms of PD, when patients lose control of their movements, is almost certainly due to the loss of dopamine nerve terminals in the striatum. 
PD symptoms feature tremors in hands, arms, legs and jaw; rigidity of limbs and trunk; slowed movement; and impaired balance and coordination. Other parts of the brain are also affected, resulting in symptoms including depression, fear, and accelerated dementia. 
While the underlying causes of PD remain unknown, three factors are proposed. Genetics probably plays a role in PD development because 15 to 20 percent of PD patients have had a close relative with the disorder.  Environmental toxins such as pesticides are also considered a cause. A population-based case-control study of 608 men and women older than 50 at the Henry Ford Health System in Detroit revealed an association between PD and occupational exposure to herbicides and insecticides.  Animal studies show that pesticides that produce free radicals damage cellular mitochondria, selectively destroy dopamine-producing neurons, and produce PD-like behavioral symptoms. 
These studies also support the third potential cause, and the most common theory, which is that PD stems from free radical-mediated degeneration of dopamine-producing cells and oxidative destruction of dopamine.
Free radicals can directly, and indirectly through toxic products that generate free radicals, damage dopamine-producing neurons and deplete cells of glutathione, an important antioxidant. Neuronal degeneration triggers inflammation, more free radicals, further neuron damage, and dopamine depletion. Post-mortem studies on the brains of PD patients show oxidative damage and mitochondrial dysfunction in the neurons of the substantia nigra. 
As people age, their endogenous antioxidant levels fall.  This may increase some individuals' susceptibility to PD and may help explain why PD tends to affect older people. Maintaining a continuously high intake of antioxidants in the diet may be a preventive measure.
Currently, the most effective means of treating PD is by replacing dopamine deficiency with levodopa (L-dopa).  Many patients on L-dopa also take carbidopa, a drug that increases the amount of L-dopa used by neurons to make dopamine. L-dopa reverses PD symptoms, prolongs patients' abilities to stay independent, and increases survival times. However, it has its limitations. After five to 10 years of L-dopa treatment, PD patients develop neurological complicationssome 40 percent develop dementia.  Researchers suspect that L-dopa's potential to generate free radicals causes further neuron degeneration during long-term treatment.  Although adequate levels of dietary antioxidants may in theory help reduce these potential toxic side effects, studies involving PD patients who supplemented with antioxidants while taking L-dopa have not shown much success. 
Researchers are looking for therapies to help slow dopamine loss in early-stage PD, to control L-dopa's long-term side effects, and to halt PD progression.  Treatment options for late-stage PD are in development, such as grafting fetal tissue into the brain to replace the lost dopamine-producing neurons, the so-called stem-cell research. 
Antioxidants and Parkinson's Disease
Antioxidants, either those made in cells or absorbed from the diet, neutralize free radicals and protect cells from oxidative injury. Among the antioxidants found inside cells are enzymes, glutathione, and Co-Q10. Dietary antioxidants include vitamins C and E, flavonoids, carotenoids, and organosulfur compounds such as those in garlic. Also important are trace minerals including copper, manganese, selenium, and zinc, which are essential for antioxidant-enzyme function.
Vitamin C and flavonoids are water-soluble; carotenoids, Co-Q10, and vitamin E are fat-soluble. Each act in different parts of the cell. For example, vitamin E acts in cell membranes, while vitamin C acts in the cell body itself, the cytosol. To effectively protect neurons in the brain, antioxidants must penetrate the blood-brain barrier and reach a sufficiently high concentration in brain tissues. In general, the blood-brain barrier is highly permeable to water, small water-soluble molecules such as vitamins, and lipid-soluble substances. It is almost totally impermeable to large, nonlipid-soluble molecules and to plasma proteins. Vitamins cross the blood-brain barrier but reach different areas with different efficiencies.
Individual antioxidants have different abilities to protect proteins, lipids and DNA. Therefore, taking antioxidants that complement one another may be more effectivefor example, vitamins C and E, or Co-Q10 and vitamin E.
Because free radicals have been implicated in PD, antioxidants should, in principle, reduce the risk of neuron degeneration and dopamine oxidation. In vitro studies support the theory that vitamins C and E suppress oxidative destruction of dopamine. 
Some human epidemiological studies indicate that people who eat more antioxidant-rich foods may have a lower risk of PD. Results, however, are inconsistent. Lifestyle factors could contribute to the inconsistency because lifestyle may play a role in PD that cannot be accounted for.
At least one compelling case has been made for vitamin E's protective effect against PD, and that's when it was consumed long-term starting in early adult years. A case-control study of 81 patients conducted in the department of neurology at the University of Medicine and Dentistry of New Jersey, New Brunswick, found low intake of vitamin E-rich foods early in life was associated with a higher PD risk. 
Vitamin E's preventive effect may extend to later years. The Rotterdam Study, conducted between 1990 and 1993, involved 5,342 independently living individuals between the ages of 55 and 95 in Rotterdam, Holland. It included 31 participants with early-stage PD. Analysis of food intake showed that daily diets containing 10 mg vitamin E reduced PD risk by half. Furthermore, the association between lowered PD risk and vitamin E intake was dose dependent. Daily intake of 1 mg beta-carotene or 100 mg vitamin C from food did not show a statistically significant protective effect. 
In contrast, a case-control-led German study comparing past dietary habits of 342 PD patients with those of 342 controls showed no difference in vitamin E intake between the two groups. However, it did show that PD patients consumed less vitamin C, niacin, and carotenoids compared with controls, though differences in carotenoid consumption were not statistically significant. The authors suggested, "If antioxidants play a protective role in this disease, the amounts provided by diet alone are insufficient."  As for niacin, interpretation was complicated by the high niacin content of coffee and alcoholic beverages, which were rarely consumed by PD patients.
The results of other observations are inconclusive with respect to vitamin E's protective role. As part of the Honolulu Heart Study, where diets of 8,006 individuals were followed for 27 to 30 years, the diets of 84 people who developed PD were compared with 336 age-matched controls. Absence of PD was associated with high consumption of legumes. Investigators selected legumes for their high vitamin E content, compared to other foods, but they concluded that there was no clear association between a diet high in vitamin E and PD prevention. 
Other epidemiological studies have shown that PD incidence correlates strongly with high dietary intake of animal fat.  High-fat diets increase the risk of free radical-induced lipid peroxidation in tissues and cell degeneration, and this finding further supports antioxidant intake to counteract these effects.
As with vitamin E, vitamin C's antioxidant properties were expected to protect against PD. An abstract showed that consumption of vitamin C, but not vitamin E, was related to lower rates of PD in women over age 50.  By contrast, as described above, consumption of diets high in vitamin E, but not vitamin C, correlated to a lower risk of PD. 
The bottom line is that antioxidants may protect against PD, but the amounts required either in the diet or via supplementation are not known clearly enough to draw significant conclusions.
Other Proposed Treatments
Because of the devastating nature of PD, the quest for improved treatments continues in many directions. One approach has been to increase internal dopamine levels by molecules that occur naturally in the body, such as nicotinamide adenine dinucleotide (NADH) and cytidinediphosphocholine (CDP-choline). Another strategy has been Co-Q10 therapy to prevent mitochondrial oxidative damage that occurs in PD patients.
Niacin and NADH, which is made from niacin, play a role in dopamine production. Studies that tested whether these supplements would benefit PD patients were small and produced conflicting results. [21, 22]
A German study of 15 patients who received an intravenous infusion of 10 mg/day NADH for seven days showed statistically significant improvement in PD symptoms.  However, patients were also given "conventional Parkinsonian pharmacotherapy," which makes one wonder if the supplement really had any effect. In addition, a double-blind study in which patients received 25 mg/day NADH intravenously for four days and an injection of 25 mg two and four weeks later showed no significant improvements either clinically or biochemically. 
CDP-Choline (citicholine) occurs in the body and is closely related to choline, a nutrient in the B-vitamin family. Some evidence suggests citicholine may enhance the effects of L-dopa, possibly by increasing dopamine levels in the brain. 
Other studies have shown CDP-choline to decrease some PD symptoms. In one German study, 85 PD patients received 1,200 mg/day oral citicholine (400 mg three times daily). Half the group took 381 mg L-dopa, the second group took half that amount of L-dopa (196 mg). After four weeks, both groups showed the same symptom improvements, suggesting citicholine treatment reduced the amounts of L-dopa needed in therapy, which may reduce L-dopa's long-term side effects. 
Co-Q10 is a component of the mitochondrial electron transport system and of energy production. It is also an antioxidant that, in animal studies, appears to provide neuroprotection. [25,26]
If neurons have a deficient mitochondrial transport system, they will conceivably produce more free radicals. Researchers have suggested this as a cause for increased oxidative damage in PD patients. In animal models of neurodegenerative diseases, impaired mitochondria have been seen in the substantia nigra and in platelets. Oral Co-Q10 treatment was found to protect the nigra and striatum of mice treated with MPTP, a free radical-producing pesticide that selectively damages the brain's nigro-striatal dopamine system. 
Platelet levels of Co-Q10 are low in patients with early-stage PD,  and Co-Q10 is well tolerated.  A pilot study at the University of California at San Diego tried to link changes in mitochondrial transport with altered PD motor activity. Researchers gave 15 PD patients 200 mg Co-Q10 one to four times daily for a month. Supplementation did not change the mean score on motor function in the Parkinson's rating system, although there was a trend for improvement in the mitochondrial transport system activity. 
The exact causes of PD are still not known. Studies in animal models and post-mortem exams of PD patients show oxidative damage plays a role in causing dopamine loss in the brain, the hallmark of PD. Clinical trials have not shown a definitive protective effect of single antioxidants such as vitamin E. However, epidemiological studies support the idea that a diet rich in antioxidantspossibly more effective when started early in life, as seen for vitamin Emay help lower PD risk and could help counteract the adverse long-term effects of L-dopa.
Antioxidant Clinical Trials
Caution In Treating PD Depression
Carmia Borek, Ph.D., a research professor at Tufts University School of Medicine in Boston, is author of Maximize Your Health-Span with Antioxidants: The Baby Boomer's Guide (Keats Publishing, 1995)
1. Mardsen CD, Fahn S, eds. The pathology of Parkinsonism. In: Movement disorders, Woburn, MA: Butterworth-Heineman 1987; p 124-65.
2. Kish SJ. Uneven pattern of dopamine loss in the striatum of patients with Parkinson's disease. NEJM 1988;318:876-80.
3. Tanner CM, et al. Parkinson's disease in twins: an etiologic study. JAMA 1999;281:341-6.
4. Gorell JM, et al. The risk of Parkinson's disease with exposure to pesticides, farming, well water and rural living. Neurology 1998;50:1346-50.
5. Tipton KF, Singer TP. Advances in our understanding of the mechanism of the neurotoxicity of MPTP and related compounds. J Neurochem 1993;61:1191-1206.
6. Dexter DT, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 1989;52:381-9.
7. Sayhoun N, et al. Carotenoids, vitamins C and E and mortality in an elderly population. Am J Epidemiol 1996;144:501-11.
8. Mardsen CD, Parkes JD. Success and problems in long-term levodopa therapy in Parkinson's disease. Lancet 1977;1:345-9.
9. Fenelon G, et al. Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Brain 2000;123:733-45.
10. Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. NEJM 1993;328:176-83.
11. Hasegawa K. The new Parkinson's disease drugs. Nippon Rinsho 2000;58:2066-71.
12. Freed CR, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. NEJM 2001;344:710-9.
13. Borek C. Antioxidants and cancer. Science Med 1997;4:52-62.
14. Khaldy H, et al. Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate on the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. J Pineal Res 2000;29:100-7.
15. Golbe LI, et al. Case-control study of early life dietary factors in Parkinson's disease. Arch Neurol 1988;45:1350-3.
16. de Rijk MC, et al. Dietary antioxidants and Parkinson's disease. The Rotterdam Study. Arch Neurol 1997;54:762-5.
17. Hellenbrand W, et al. Diet and Parkinson's disease II: a possible role for the past intake of specific nutrients. Results from a self-administered food frequency questionnaire in a case-control study. Neurology 1996;47:644-50.
18. Morens DM, et al. Case-control study of idiopathic Parkinson's disease and dietary vitamin E. Neurology 1996 46:1270-4.
19. Anderson C, et al. Dietary factors in Parkinson's disease: the role of food groups and specific foods. Mov Disord 1999;14:21-7.
20. Cerhan JR, et al. Antioxidant intake and risk of Parkinson's disease (PD) in older women. Am J Epidem 1994;139:S65 (abstract).
21. Kuhn W, et al. Parenteral application of NADH in Parkinson's disease: clinical improvement partially due to stimulation of endogenous levodopa biosynthesis. J Neural Transm 1996;103:1187-93.
22. Dizdar N, et al. Treatment of Parkinson's disease with NADH. Acta Neurol Scand 1994;90:345-7.
23. Garcia-Mass A, et al. Effects of citicholine in subcortical dementia associated with Parkinson's disease assessed by quantified electrocephalography. Clin Ther 1992;14:718-29.
24. Eberhardt R, et al. Citicholine in the treatment of Parkinson's disease. Clin Ther 1990;12:489-95.
25. Russel T, et al. Coenzyme Q10 administration increases brain mitochondrial concentration and exerts neuroprotective effects. Proc Nat Acad Sci 1998;95:8892-7.
26. Gotz ME, et al. Altered redox state of platelet coenzyme Q10 in Parkinson's disease. J Neural Transm 2000;107:41-8.
27. Shults CW, et al. A possible role of coenzyme Q10 in the etiology and treatment of Parkinson's disease. Biofactors 1999;9:267-72
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