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.
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.
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.
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.
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.
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.
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.
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.
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.
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.