Parkinson’s Disease

Parkinson’s Disease (PD), described over 180 years ago, is a common disease, affecting 3% of the population over 65 years old in the United States (Lang and Lozano, 1998). The dopaminergic neurons of the substantia nigra are selectively and progressively destroyed above and beyond the decrease exhibited in the usual aging process. Many epidemiological studies have linked exposure to environmental toxins with increased risk of disease

Pesticide exposure, both occupational and in-home, including insecticides and herbicides, has been associated with parkinsonism in numerous studies. A strong association between occupational exposure to organochlorines and alkylated phosphates and the disease has been shown (Seidler et al., 1996). In a meta-analysis of nineteen studies, the majority showed a consistently elevated risk of PD with pesticide exposure, and the risk increased with additional years of exposure (Priyadarshi et al., 2000). Rural residence (Gorell et al., 1998; Ho et al., 1989; Golbe, 1998), agricultural work (Semchuk et al., 1992; Gorell et al., 1998; Ho et al., 1998; Golbe, 1998) and well water use (Gorell et al., 1998) have increased odds risks in other studies. Pesticides are very chemically diverse compounds with a multitude of biochemical effects so relative risk estimates from the whole category of pesticides would tend to underestimate the risk by including exposure to non-parkinsonigenic compounds

Other studies have shown increased risks related to other exposures or toxins. Patients with the disease had a significantly increased number of mercury amalgams in one study (Seidler et al., 1996). Occupational exposure to manganese, lead or copper or to dual combinations of lead, iron and copper have been correlated with increased risk (Gorell et al., 1999). Wood preservative use (which can involve heavy metals, volatile organic compounds and hydrocarbons) was seen to increase odds of developing PD (Seidler et al., 1996). Carbon monoxide and carbon tetrachloride poisonings (Peters et al., 1988) can be etiologic agents in PD.

A variety of toxins, both exogenous and endogenous, have been shown to be specifically destructive to nigral dopaminergic cells. Meperidine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenous use has lead to an irreversible PD in a number of users (Davis et al., 1979; Langston et al., 1983). MPTP produced PD in several primate species (Burns et al., 1983) as well. Post-mortem studies confirmed that specific destruction of the substantia nigra dopaminergic neurons had occurred in both humans and primates exposed to MPTP. Positron emission tomography (PET) studies in human MPTP users demonstrated that the dopamine concentration in the SN must drop by 80% before symptoms appear (Calne et al., 1985). It appears that destruction of the SN cells by neurotoxins, which may occur years before symptom development, when superimposed on the attrition of dopaminergic cells normally seen in aging, creates a critical threshold where the reduced cell numbers are no longer able to physiologically compensate. Paraquat (an herbicide) and rotenone (a naturally occurring and widely used pesticide) have chemical structures similar to MPTP and have been associated with the development of PD (Liou et al., 1997; Hertzman et al., 1990). Chronic, systemic exposure of rats to rotenone produced systemic inhibition of complex I, also associated with SN dopaminergic destruction and behavioral changes mimicking PD (Betarbet et al., 2000). Chronic exposure to maneb (a manganese-containing fungicide) has been reported to lead to parkinsonism in humans (Meco et al., 1994; Ferraz et al., 1988). Exposure of rats to a combination of paraquat and maneb but not to either of the single compounds, caused a loss of the dopaminergic neurons of the SN and behavioral changes mimicking PD (Thiruchelvam et al., 2000). This study suggests that exposure to mixtures of chemicals may be synergistic in the etiology of PD.

Case studies have documented acute parkinsonism following organophosphate (OP) exposure (Bhatt et al., 1999) as well as PD in a pesticide applicator with numerous documented poisonings from OP pesticides (Davis et al., 1978). OP’s are cholinergic and it is established that PD is correlated with a relative imbalance of cholinergic to dopaminergic activity. Pharmacologic increases in cholinergic activity have been reported to produce parkinsonism. Common treatments block the action of acetylcholine (ACh) with anticholinergics and/or increase dopamine concentrations with L-dopa. As with many age-related diseases, PD seems to be a multifactorial disease, in which genetic factors interact with environmental factors (Calne and Langston, 1983). Although environmental agents seem to be associated, clusters of PD patients have not been found.

As more work is done on the genetics of those with PD, it is hypothesized that defects in the enzyme detoxification systems of susceptible individuals may potentiate neurotoxic exposures, making those individuals more susceptible to exposures that would not cause the disease in others. Glutathione transferases (GST’s) are detoxification enzymes involved in the conjugation of glutathione with pesticides and a wide variety of environmental toxins. A study, which investigated the role of GST and pesticides in PD patients and controls, found that the GSTP1 genotype was significantly different between patients and controls exposed to pesticides (Menegon et al., 1998). ). Another study found a greater susceptibility to PD in males with a deletion of the GSTM1 gene (Stroombergen and Waring, 1999). Although a large twin study concluded that genetic factors were not the major factor in the etiology of idiopathic parkinsonism (Tanner et al. 1999) it seems clear that genetic factors do play a part in the risk factors connected with the disease. Having a close relative with the disease is one of the strongest predictors of the disease (Semchuk et al., 1993

Standard treatments of PD have been primarily palliative. At this point, six categories of drugs are the principle agents used. Anticholinergics serve to balance the relative imbalance between DA and ACh and may also prolong the action of DA by inhibiting its reuptake. They are usually used for their action in decreasing tremor and in combination with levodopa. Use is often limited by their side effects. The antiviral, amantidine, is used in mild cases and early in the disease, and its action is believed to result from stimulating release of DA from remaining dopaminergic neurons in the SN. It can delay the time before the use of levodopa is instituted. Selegeline, a monoamine oxidase-B (MAO-B) inhibitor, prevents the breakdown of DA and may extend the action and duration of levodopa (Semenchuk, 2000). It also has antioxidant action and has been shown to delay the progression of the disease, as well as an ability to inhibit MPTP breakdown into neurotoxins (Fahn, 1991). Selegeline is typically used alone in early stages and later combined with levodopa. DA agonists mimic the activity of the neurotransmitter and are considered the most effective agents after levodopa. Although their use was originally as an adjunct to levodopa in advanced cases (and pergolide is still used in this manner), the newer agents pramipexole and ropinirole are now often used alone in early-stage PD and may delay the use of levodopa for years. Levodopa is to date the most effective drug in the treatment of PD symptoms. It is the metabolic precursor of DA and is usually combined with carbidopa. The combination is synergistic and minimizes adverse side effects. This therapy is usually instituted when PD symptoms begin to interfere with the activities of daily living (Semenchuk, 2000). Levodopa therapy has serious complications and there is evidence, although to date no definitive clinical studies in humans, that it may accelerate some of the pathogenic factors in PD. It may increase oxidative stress in the dopaminergic neurons, conceivably leading to earlier disability and death. Evidence that supports this includes that levodopa causes increased oxidative stress in cell cultures of “normal” dopaminergic neurons and that tissue cultures of the neurons of PD patients exposed to levodopa showed marked neurotoxicity (Mena, 1992).

Given the likelihood that environmental exposures could be contributory to the neurotoxicity exhibited by PD patients, this clinic investigated the effect of intensive depuration therapy to rid the body of environmental toxins in diagnosed PD patients exhibiting toxicity, as documented by serum tests for organochlorine pesticides and solvents, and post-DMPS urine catch for heavy metals.

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