Pathology
Most clinical manifestations of parkinsonism
seem to be connected to the loss of striatal dopamine due
to dopaminergic cell death. Because surviving
dopaminergic neurons are able to compensate for the loss
of others, there must be an eighty to ninety percent
decrease in striatal dopamine to produce any clinical
manifestations. In the initial stages of parkinsonism
the number of dopamine receptors increases, which offsets
the loss of dopamine. However, as it progresses the
number of receptors decreases, probably because of the
degeneration of dendritic spines on striatal neurons
(Yurek 1993).
In order to pathologically diagnose Parkinson's
disease, laminated inclusions called Lewy bodies must be
found in two 7mm hemisections of the substantia nigra.
The round, eosinophilic inclusions are 7 to 20 nm in
diameter. They are composed of tubulin and
microtubule-associated proteins 1 and 2. Because Lewy
bodies are commonly found in the brain due to other
diseases, as well as five to ten percent of non-diseased
brains, the mere presence of Lewy bodies is not
sufficient to make a positive diagnosis. However, a
concentration of Lewy bodies in the substantia nigra is
unique to parkinsonism.
Positive pathological diagnosis also requires
a loss of melanin-containing neurons in the pars
compacta. In addition, degeneration of the mesostriatal
pathway (the neurons projecting from the mesencephalon
to the putamen, caudate nucleus, and nucleus accumbens)
occurs in most cases of parkinsonism. Though there is
neuronal degeneration in other areas of the
extrapyramidal system, neuronal loss is concentrated in
the mesostriatum. For unknown reasons dopamine depletion
of the substantia nigra is greatest in the central
regions while the medial regions are almost unaffected
(Yurek and Sladek 1993).
Dopamine Reception and Regulation
There are five known classes of dopamine
receptors in the brain (D1, D2, D3, D4, D5) but only D1
and D2 seem to be involved in parkinsonism. Dopamine
receptors are glycoproteins which contain seven
membrane-spanning helices (see Figure 4). Most dopamine
receptors are metabotropic-- dopamine binds to the
extracellular interface, and the intracellular interface
activates intracellular proteins. Recent studies of
messenger RNA and gene regulation suggest that some
dopamine receptors might be genotropic (McGreer and
McGreer 1993).
The most abundant type of receptors in the
striatum belong to the D1 class. Dopamine binding by D1
receptors causes G-protein activation. Activated
G-proteins activate adenylate cyclase, which catalyses
the production of cyclicAMP from ATP. The action of
cyclicAMP within the neurons is not known. It is also
not known if therapeutic activation of D1 receptors leads
to useful effects, undesirable effects, or both.
Although D2 receptors do not appear to coexist
on the same neurons with D1 receptors, D2 receptors are
found in the same nuclei as D1 receptors. D2 receptors
are not associated with adenylate cyclase, rather they
act through phosphoinositide hydrolysis (McGreer and
McGreer 1993). When activated they cause a reduction of
intracellular cyclic AMP concentrations, open potassium
channels, and close calcium channels.
Early research on dopamine receptors focused on
the D1A and D2A subtypes in the striatum, but recent
studies suggest that other receptors in different nuclei
could play an important role in parkinsonism. Some
evidence suggests that there is a direct interaction of
D1 and D2 receptors. Walters et al. showed that D1
stimulation is required for the expression of activated
D2 receptors (1987). D3 and D4 receptors probably have
functions similar to D2 receptors, and D5 types are
similar to D1 receptors. Some presynaptic D1 receptors
are located in the substantia nigra to receive dendritic
dopamine release (Matthews and German 1986, cited in
Yurek and Sladek 1990). According to Yurek and Sladek,
dendritic dopamine release may be a local feedback system
for nigral dopamine neurons (1990). Therefore,
therapeutic restoration of dopamine may not completely
make up for neuronal loss because the dopamine receptors
of the nigral neurons will have been lost as well,
rendering the feedback mechanism unable to function.
A striatonigral negative feedback loop is the
key contributor to dopamine activity regulation. Neurons
from the putamen and caudate nucleus project substance P
and GABA fibers to the pars compacta. Substance P
projections excite the substantia nigra causing an
increase in dopamine release while GABAergic fibers
inhibit dopamine release. Groves found that degeneration
of the dopamine system stimulates substance P release and
inhibits GABA release, which causes compensatory
increases of nigral dopamine released to the striatum
(1983, cited in Yurek and Sladek 1990). Groves also
postulates that the remaining dopamine should have a
longer half life because of the aforementioned increase
in dopamine release from surviving neurons, a decrease in
presynaptic dopamine uptake sites, and a decrease in
presynaptic metabolic enzymes (1983, cited in Yurek and
Sladek).
Theories of Dopaminergic Neuronal Loss
Many theories on dopaminergic neuronal loss
have been proposed but most have been refuted based on
unsuccessful therapeutic results. One of the earliest
hypotheses was based on autoimmune disorders. However,
immunotherapy has not been shown to be beneficial. The
theory of excessive excitatory drive of the basal ganglia
has also not been supported with much evidence. Some
researchers believe that there is a possibility that
abnormalities of neurotrophic factors play a role. Three
trophic factors are known to exist in the brain: nerve
growth factor (NGF), fibroblast growth factor (FGF), and
epidermal growth factor (EGF). However, no evidence has
shown that they play roles in the development or
progression of parkinsonism. The potential of calcium
overload is currently being investigated as a contributor
to the progression of parkinsonism but it has not been
overwhelmingly implicated as a dominant factor causing
parkinsonism. Enzyme abnormalities resulting in
impairment of toxin metabolism (e.g. cytochrome P450)
have been suggested and the results of relevant tests are
pending. Theories involving genetic factors,
environmental factors, and toxic free radicals are
currently receiving the most attention.
Research in the genetics of Parkinson's disease
has produced conflicting results. Most studies show no
correlation to genetics but some studies have resulted in
contrary findings. Jankovic and Reches studied
monozygotic twins and found no genetic correlation to
Parkinson's disease (1986, cited in Stacy and Jankovic
1992). However, Roy et al. found ten families with
akinetic rigid parkinsonism that fit an autosomal
recessive pattern of inheritance (1983, cited in Stacy
and Jankovic 1992). Golbe et al. studied two large
families, with parkinsonism proven upon autopsy, that fit
an autosomal dominant pattern of inheritance (1990, cited
in Stacy and Jankovic 1992). As of yet there is no
consensus on the role of genetics in Parkinson's disease.
There are many factors supporting the theory of
environmental involvement. It is strongly supported by
the MPTP model, but no environmental toxins have been
implicated. Because MAO inhibitors alone do not work
well to combat the onset or progression of Parkinson's
disease or MPTP-induced parkinsonism, the production of
MPP+-type molecules is probably not completely correct.
Other data supportive of the environmental hypothesis are
that Parkinson's disease is more prevalent (though
unexplained) in rural areas, regions where well water is
consumed, and where people are exposed to pesticides and
herbicides. The causal agent of MPTP-induced
parkinsonism (MPP+) is used as an herbicide (cyperquat).
D'Amato et al. found that Caucasians are four
times more likely to get Parkinson's disease than are
darkly pigmented races (1987). They conclude that just
as MPTP is known to be tightly bound by melanin-
containing neurons of the substantia nigra, cutaneous
melanin could bind environmental toxins, thus preventing
them from crossing the blood-brain barrier (D'Amato et
al. 1987). Other environmental factors implicated by
Jankovic et al. in inducing parkinsonism are carbon
monoxide, manganese, carbon disulfide, cyanide, and some
types of encephalitis (1990).
The most encouraging theory involves toxic free
radicals. Free radicals are known to have mutagenic
properties as well as cause lipid peroxidation which
breaks down cell membranes and leads to neuronal death.
(Olanow 1990). There are many arguments for the natural
occurrence of free radicals in the brain. Hirsch et al.
note that the by-products of melanin production
(oxidative metabolism of catecholamines) include hydrogen
peroxide, superoxide anions, and hydroxyradicals (1989,
cited in Stacy and Jankovic 1992).
Elemental iron, which is known to increase free
radical formation in the nervous system, is found in high
concentrations of brains of Parkinson's disease patients
(Olanow 1990). Chiueh et al. studied the ability of iron
to promote dopamine auto-oxidation and found that it
leads to the formation of cytotoxic quinones and OH free
radical (1993). They suggest that OH free radicals
directly contribute to degeneration of A9 nigrostriatal
neurons (where iron is present) and indirectly contribute
to calcium overload and potassium overflow (Chiueh et al.
1993). Mitochondria are presumed to be especially
susceptible to mutagenesis by free radicals because they
lack protecting histone proteins and DNA repair
mechanisms (Stacy and Jankovic 1992).
The Parkinson Study Group has found that
vitamin E, a potential scavenger of free radicals, has no
therapeutic value in parkinsonism (1993). However, this
does not disprove the free radical hypothesis because it
is possible that vitamin E does not enter the substantia
nigra or striatum, or it does not act on all types of
free radicals and similar molecules. Currently, in the
Deprenyl and Tocopherol Antioxidative Treatment of
Parkinsonism (DATATOP) study, the protective effects of
antioxidants are being tested.
Using MPTP as a model, chemicals endogenous to
the brain have been searched for which have the potential
for dopaminergic neurotoxicity and are specifically
concentrated in the dopaminergic neurons of the
substantia nigra. Recent discovery of a molecule called
1,2,3,4-tetrahydroisoquinoline (TIQ, see Figure 6) could
prove to be a major breakthrough. TIQ is formed
endogenously by the condensation of dopamine with an
aldehyde or keto acid, followed by decarboxylation and
reduction (Naoi et al. 1993). Very promising results
were obtained by Naoi et al. They found many
similarities between MPTP and the N-methylated form of
TIQ, N-methylTIQ (NMTIQ). Interestingly, they also
noticed that MAO (which is concentrated in dopaminergic
neuronal mitochondria) catalyses the conversion of NMTIQ
into N-methyl isoquinolinium ion (NMIQ+), a neurotoxic
molecule very similar to MPP+ (1993). Activity of N-
methyltransferase, the enzyme which converts TIQ into
NMTIQ, was found to be greatest in the substantia nigra
(1993). These results suggest that at least one source
of idiopathic Parkinson's disease has possibly been
found.
