Write an essay on Parkinson’s disease and its treatment

March 2003: Write and essay on Parkinson’s disease and its treatment.

March 2005: What are the limitations of L-DOPA therapy in Parkinson’s disease?
Discuss alternative treatment strategies.

March 2006: What are the neurological defects that characterise Parkinson’s disease and
how might this condition be treated?
 In 1817, James Parkinson wrote ‘An Essay on the Shaking Palsy’ which was the
first description of the clinical symptoms of Parkinson’s disease (PD). This is a slow
progressive neurodegenerative disorder and the clinical manifestations of PD include
rhythmical tremors at rest, cogwheel rigidity, akinesia (difficulty in initiating movements)
and bradykinesia (slow execution of movement). Our understanding of the neurochemical
changes behind PD stems from a discovery made in 1960 by Hornykiewicz. By
examining postmortem brains of PD patients, Hornykiewicz showed that the substantia
nigra and corpus striatum contained significantly reduced levels of dopamine (DA) due to
loss of dopaminergic neurons in the substantia nigra. Following on from this discovery,
Hornykiewicz and Birkmayer went on to hypothesize that PD can be treated by restoring
normal dopaminergic levels. Indeed, the first-line treatment for PD is L-3,4-
hydroxyphenylalanine (levodopa) which is converted into dopamine by remaining
dopaminergic neurons in the brain. However, levodopa is limited in its therapeutic use for
PD because its effectiveness declines as PD progresses. Therefore we must be prepared to
develop alternative treatment strategies and one such example is an experimental
technique involving neurotransplantation of fetal midbrain neurons directly into the
striatum.

P.653 Fig. 42.5 Kandel and Swartz

Dopaminergic neurons in the substantia nigra excite the direct pathway and
inhibit the indirect pathway by which cortical inputs to the neostriatum are mediated
through the basal ganglia to the thalamus. Activation of corticostriate nerve fibres excites
the direct pathway by stimulating striatal neurons which inhibits basal ganglia output
nuclei globus pallidus internal segment and substantia nigra pars reticulate) and hence
lead to disinhibition of thalamic cells. Consequently, activation of thalamocortical
neurons excites premotor and supplementary motor areas thus the direct pathway
facilitates movement. However, corticostriatal activation also excites the indirect
pathway which inhibits movement. Excitation of striatal neurons inhibits the globus
pallidus external segment leading to disinhibition of subthalamic nucleus and thus
excitation of basal ganglia output nuclei in contrast to the direct pathway. The balance
between the direct and indirect pathways regulates motor control and it is this balance
which is disrupted in PD. The dopaminergic neurons in the substantia nigra excite the
direct pathway and inhibit the indirect pathway thus dopamine facilitate movement by
acting on both pathways. This explains how loss of dopaminergic neurons in PD leads to
akinesia, bradykinesia and the shuffling gait presented by PD patients.

Our understanding of the neurotransmitter role of dopamine allows us to devise

therapeutic strategies that restore the actions of dopamine in PD patients. The primary
treatment for PD is levodopa which is a dopamine precursor that crosses the blood brain
barrier where it is converted into dopamine by dopa decarboxylase. Levodopa acts either
by increasing the amount of dopamine released by remaining dopaminergic neurons or
simply by raising the concentration of exogenous dopamine in the striatum because non-
dopaminergic cells can also express DOPA-decarboxylase. Carbidopa, a dopa
decarboxylase which cannot cross the blood brain barrier, is administered with levodopa
to prevent peripheral metabolism of levodopa into dopamine. Entacapone, an inhibitor of
catechol-O-methyl transferase (COMT), is also administered with levodopa as it inhibits
dopamine degradation. Unfortunately, although levodopa is the most effective treatment
for PD, it also has many side effects. Acute side effects of levodopa include nausea,
anorexia, hypotension, delusions, hallucinations, disorientation, insomnia or nightmares.
After 2 years of levodopa treatment, most patients develop dyskinesia (involuntary
writhing movements) especially in the face and limbs. Patients treated with levodopa may
suffer rapid fluctuations where hypokinesia and rigidity may suddenly worsen giving an
‘on-off’ effect. The major limitation of levodopa therapy however, is that it does not alter
the course of PD and its effectiveness declines as PD progresses.

If the effectiveness of levodopa therapy in treating PD is limited, what other

forms of treatments are available to clinicians? In 1982, seven young drug addicts in
California developed PD when they took heroin contaminated with 1-methyl-4phenyl-
1,2,3,6-tetrahydropyridine (MPTP). It was later found that MPTP is neurotoxin which is
converted into a toxic metabolite MPP+ by monoamine oxidase B (MAO-B). MPP+ is
then transported into dopaminergic neurons where it inhibits mitochondrial oxidation
reactions causing oxidative stress and death of substantia nigra dopaminergic neurons.
When MPTP is injected into animals, they display symptoms of PD and this has led to
useful animal models of PD. Selegiline, a selective MAO-B inhibitor, is now an adjunct
therapy for PD by protecting dopaminergic neurons from intraneuronal degradation.
Bromocryptine is a dopamine (D2) receptor agonist which helps ameliorate PD symptoms
and reduce the levodopa dosage required. Amantadine also has antiparkinsonic effects
and may act by increasing dopamine release but its mechanism of action is not entirely
clear. In PD patients being treated with antipsychotic drugs, levodopa is not used because
antipsychotic drugs are dopamine antagonists. Instead, these patients are administered
with muscarinic acetylcholine (ACh) receptor antagonists, e.g. benzatropine, which
prevent ACh from opposing the effects of dopamine on striatal neurons and inhibiting
dopaminergic nerve terminals presynaptically via muscarinic receptor activation.

Finally, an experimental technique being developed to treat PD is neural

transplantation (see Barker & Rosser, 2001). In rodents with degenerated nigrostriatal
dopaminergic pathways, transplantation of immature dopaminergic neurons from the
mesencephalon of 13-15 days old rat foetuses into the denervated striatum was shown to
restore dopamine synthesis and release in the reinnervated region. This confirmed that
cell replacement of dopaminergic neurons is a possibility and this technique gained
further support when postmortem studies on patients who had fetal dopaminergic cells
transplanted into their striatum showed that these transplants are capable of surviving and
forming synapses. Unfortunately, results from neural transplantation trials are variable
but it is hoped that a greater understanding of how graft location, age of donor tissue,
preparation methods affect the survival of transplanted dopaminergic cells will lead to
improved success rate.

NEED MORE BRAIN STUFF, basal ganglia function and circuitry AND LESS
DRUGS?
WOULD LIKE MORE DISCUSSION ON ALTERNATIVE TREATMENTS, FIND
BIG BOOK OF DRUGS?