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A case-control study of Parkinson's disease (PD) was conducted in the city …

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- Genetics, drugs and environmental factors in parkinson's disease (A case-control study)

Rural living, potable well-water source, trauma, and herbicides/pesticides variables were considered as of irrelevant statistical value. Due to contradictory studies about a possible protective action of cigarette smoking against PD, a broad survey about the possible protective action of cigarettes in case of PD18 is deemed necessary. After analyzing 46 studies related to this issue, using the statistical method, one may come to the conclusion that cigarette smoking is capable of protecting against PD. According to the authors, it would be possible that some tobacco component could act as a protection for neurons against ambient toxins.

Univariate analysis showed only a slight cigarette protective action against PD. In stratified analysis, the use of drugs among non-smokers was found to be responsible for a decrease of approximately 40% of the odds ratio. On the other hand, it did not present variation when confronted with smokers. Otherwise, if the cigarette consumption odds ratio is analyzed only among those that made use of drugs, there is a small reduction from 0.39 to 0.24. Still, there is a moderate increase in the cigarette smoking odds ratio if considered among those who did not make use of parkinsonian drugs. It could be also verified that family history odds ratio shows a decrease of 20% when considered among non-smokers, the opposite occurring among smokers, and in this case, there is an increase of approximately 42%. Although, as noted in a restricted number of cases, these results seem to increase the possibility of cigarettes having a protective action against the development of the disease. But, if it is really so, it is more related to those cases where external toxins and family history have some participation. As possible corroboration to this finding, there is a study on cigarette protective activity in drug-induced parkinsonism19.

Bibliographical revision about the role of heredity in PD conferred upon it an autosomal character of the dominant kind with reduced penetration20. Reports of familial cases indicated a higher genetic participation in PD21. The possibility of simultaneous exposure to the action of environmental toxins within the same family was observed among hypotheses for genetic participation in PD21. It does seem possible that, in some cases, some kind of genetic mutation might have occurred which led to the onset of PD in the individuals affected.

In the present study, from the viewpoint of causality, univariate and multivariate analysis pointed to family history as a PD risk factor. In the group of subjects, 19 cases (20.65%) were noted. Results reflect previously reported studies and this fact could possibly be explained if one observes that some subjects had a previous history of drug-induced parkinsonism, as it can be noted in some reports3,4. Thence, when genetic analysis of parkinsonian syndrome was effected, it became a complex task to distinguish cases of drug-induced parkinsonism from PD itself. Martin et al.22 postulated that the mechanism of drug-induced parkinsonism can be related to PD. In other words, some patients presenting such transitory syndrome are perhaps also indicating some kind of genetic predisposition to PD. According to the authors, some individuals affected by transitory parkinsonism might present an inadequate activity of the tyrosine hydroxilase enzyme. This hypothesis was based on a study by Chase et al.23 that observed low levels of homovanillic acid in parkinsonian patients, after these patients had been treated with phenothiazine. On the other hand, the levels of mentioned acid were found to be high among individuals not presenting the syndrome.

Another aspect to be considered in relation to a predisposition for PD in some patients with drug-induced parkinsonism refers to the cytochrome P-450 hepatic enzymatic family, whose deficiency of the hydroxylation mechanism of the debrisoquine substance has been described in at least 75% of the patients with PD24. Also, it is known that this failure is related to the autosomal recessive heredity that is mediated by the mutant allele "n". So, it would not be surprising to expect that some drugs with xenobiotic behavior could be responsible for an abnormal accumulation of these substances in the blood of patients presenting difficulties to metabolize them.

The negative aspect found in relation to herbicides and pesticides could be possibly related to the field study area, with an irrelevant agricultural productivity. A study showed that mentioned substances can trigger parkinsonism25. Many epidemiological investigations have been directed towards the search for an environmental substance whose structure and action mechanism would be similar to MPTP. One of the aspects that could influence the toxicity of such agents seems to be related to an individual predisposition for the development of PD. The hypothesis that points to the premature onset of the disease in some patients might perhaps explain the higher sensibility of such individuals to the action of mentioned substances24, just because of the higher number of inherited failures of the recessive kind for the hepatic hydroxylation function.

Most reports mentioning the association between chemical agents and parkinsonism denote isolated cases, in general with complete remission of the parkinsonian syndrome4. One of the exceptions is the appearance of symptoms similar to PD when related to MPTP7,26. Some very controversial data can be found in epidemiological literature about the role of chemical agents in PD. Semchuck et al.27 could not obtain positive results for analyzed factors in relation to the following items: mineral oil, aluminum, carbon monoxide, cyanide, manganese and mercury. Tanner et al.28, in a study carried out in China, attributed the low number of cases in that country to the lack of technological development in agriculture. A case-control study conducted with the multiethnic population of Singapore found high levels of mercury in both urine and hair of patients with PD29. Recently, Gorell et al.30 found positive results in a group of patients who were in contact with metals for more than 20 years of occupational activity. Participation of such metals was made evident by the obtained values odds ratio for copper (OR = 10.61%; CI = 1.06, 105.83). It also became evident that combinations of metals such as steel/copper, steel/iron and copper/iron increased PD risk. Authors believe that the presence of such metals could have favored an increase in the generation of free radicals in the substantia nigra.

The first account of transitory parkinsonian syndrome following petroleum intoxication was published in 199431. Among petroleum components, pyridine, toluene and benzene can be found, and all these compounds cause parkinsonian effects. Previous descriptions mentioned petroleum components as being responsible for isolated cases4. In five cases there was a history of chronic exposure to petroleum products. Univariate and multivariate analysis confirmed an association with chemical agents, demonstrating a discreet presence of this variable for PD risk. Positive family history was found in 5 of the 14 cases obtained in relation to such substances.

In 1982, Rajput et al.32 described anatomopathological findings of two cases with previous history of neuroleptic-induced transitory parkinsonism. Necropsy findings showed PD characteristics, which led the authors to postulate that such individuals already had the disease in a pre-clinical state when parkinsonian manifestations started to occur. The publication referring to the three cases with initial parkinsonian diagnosis was replaced by PD itself, also led to the hypothesis that these patients presented sub-clinical PD when symptoms occurred. Some authors warned about a possible participation of drugs with parkinsonian effect in the genesis of PD14,33. Notwithstanding, none of the epidemiological studies considered the use of drugs as a risk factor for PD. On the contrary, what can be noted in many papers, is the fact that patients that make or made use of medication with parkinsonian action are not taken into consideration. The exclusion of this factor in epidemiological studies of PD is perhaps related to the strict control regarding over-the-counter sale of medication in the countries where such investigations were carried out. Conversely, it was not by chance alone that the first cases of calcium-antagonist-induced parkinsonism were reported in Brazil and in Uruguay34,35, countries where a strict control regarding the use of medicines is inexistent.

Some studies about the metabolism of neuroleptics demonstrated that such drugs, besides having a similar structure to MPTP, also form MPP+ similar compounds in their catabolism36. Moreover, they are also capable of causing damage to the respiratory enzymatic chain11 and to the substantia nigra itself13. The respiratory enzymatic chain can be affected in the same way, both in PD and in the toxic injuries provoked by MPTP, neuroleptics, and calcium antagonists. It seems acceptable that drugs capable of altering the dopamine metabolism, an indispensable neurotransmitter to cellular physiology, may also have some kind of repercussion upon the survival of dopaminergic neurons. Evidence of a 20% reduction in the activities of Complexes I and II/III in the mitochondria of untreated patients with PD contribute to this hypothesis37. This indicates that this kind of alteration can be aggravated if in the presence of substances with the same effect, as reported in other studies11,12. In the same way, calcium antagonists may also be aggressive to the respiratory enzymatic chain12. Furthermore, this group of drugs has a blocking competitive action of D2 receptors in the striatum38 that would facilitate the expression of parkinsonian symptoms.

Some studies report a low assimilation of F-dopa in the putamen of patients with persistent parkinsonism, when triggered by neuroleptics. In elderly patients affected by this syndrome, the appearance of an hyperintensity image in the nucleus caudatus was reported39. Another study, using MRI, made evident that the images of hypointensity in the putamen were predominant in youngsters, while those of hyperintensity in the striatum could be observed in elderly patients40. According to the authors, the presence of hypointensity images in the putamen of young patients could be related to a direct and toxic effect of this kind of drug, while the images of hyperintensity in the striatum observed in elderly people, were maybe related to vascular factors, depending on the age of such patients. The eventual participation of drugs favoring higher levels of iron deposit in basal ganglia can be also observed41, a fact that would favor this metal turnover. Through positron emission tomography, it has been recently demonstrated that isolated loss of dopaminergic terminals in the posterior putamen suffices to the expression of the motor manifestations of the disease42.

The present study seems to support the hypothesis that genetic and exposure to drugs or chemical agents with secondary parkinsonian action is associated with an increased risk for PD.

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