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Mr J.McGrath, 2008
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Protect; Restore; Replace; Stimulate: Parkinson’s Disease in 2020
Introduction
Parkinson’s Disease (PD) is a slowly progressive degenerative disease of later life
caused by death of dopamine producing neurons within the substantia nigra of the
brain’s basal ganglia. Loss of dopamine results in abnormal nerve firing patterns
within the brain that cause impaired movement and the characteristic symptoms of
PD- tremor, rigidity, and bradykinesia. Today, about 130,000 people suffer from PD
in the UK and the aging population means the management of PD will prove an
increasingly important and challenging part of medical practice.
Considerable advances made in defining the aetiology, pathogenesis and pathology of
PD have resulted in the development and expansion of the pharmacopoeia available
for treatment. Current therapy options for PD remain focussed on the symptomatic
control and improvement of motor features rather than cure. Dopamine replacement,
either precursors or mimics, improves motor function, significantly reduces both the
morbidity and mortality of PD and improves quality of life.1 Levodopa remains the
most commonly used drug in PD. It is effective in improving bradykinesia and
rigidity, but does result in motor complications including dyskinesias and ‘wearing
off’. 2
This essay asks what the future holds for the treatment of PD. In the 200 years since it
was first described, there have been considerable advances in our understanding.
Biochemical abnormalities including mitochondrial dysfunction, free radical
mediated damage, and inflammatory changes have all been identified in the PD brain.
Importantly, these abnormalities have provided targets for potential novel drug
therapies. In recent years, advancing research has made halting the progression of PD,
restoring lost function, and even preventing the disease realistic goals. 3 This essay
gives a brief overview of current lines of research and highlights some potential novel
therapies.
Slowing progression?
The neurodegeneration in PD seems to result from cellular processes such as
mitochondrial function deficiency, increased oxidative stress, apoptosis,
excitotoxicity, and inflammation; however, the actual cause of the dopamine cell
death is undetermined. Studies have shown that most PD patients have lost at least
60-80% of the dopamine-producing cells in the substantia nigra by the time
symptoms appear. Neuroprotective drugs may slow the progression of neuron loss
and hence PD onset. One study, NET-PD (Neuroexploratory Trials in Parkinson's
Disease), is evaluating a range of mitochondrial enhancing drugs, anti-apoptotic and
anti-inflammatory drugs to determine if any of these agents should be considered for
further testing. The NET-PD study may evaluate other potential neuroprotective
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agents in the future. Drugs found to be successful in the pilot phases may move to
large phase III trials involving hundreds of patients.
Several of the most promising lines of investigation include the antioxidant coenzyme
Q10 (ubidecarenone) and anti-apoptotic agents such as CEP-1347. Studies in patients
with PD with coenzyme Q10 have suggested that it slows functional decline. The
PRECEPT study is currently assessing the neuroprotective role of CEP-1347 in the
early phase of the disease. 3 Several MAO-B inhibitors, including selegiline, are also
in clinical trials to determine if they have neuroprotective effects.
Further research is focusing on how inflammation affects PD. Inflammation is
common to a variety of neurodegenerative diseases, including PD, Alzheimer's
disease, and Motor Neuron Disease. Several studies have shown that inflammationpromoting molecules increase cell death after treatment with the toxin MPTP.
Inhibiting the inflammation with drugs or by genetic engineering prevented some of
the neuronal degeneration in these studies. Other research has shown that dopamine
neurons in brains from patients with PD have higher levels of the inflammatory
enzyme COX-2 than those of people without PD. Inhibiting COX-2 doubled the
number of neurons that survived in a mouse model for PD. 4
Genetic Therapy?
Scientists have identified several genetic mutations associated with PD, and other loci
await refinement and characterisation. Studying the genes responsible for inherited
cases of PD will help researchers understand both inherited and sporadic cases. The
same genes and proteins that are altered in inherited cases may also be altered in
sporadic cases by environmental toxins or other factors. Identifying gene defects can
help researchers understand how PD occurs, develop animal models that accurately
mimic the neuronal death in human PD, identify new drug targets, and improve
diagnosis.
Gene therapy is an exciting arena and includes potentially neuroprotective and
neurorestorative agents. A clinical trial aiming to replace GABA, an inhibitory
neurotransmitter with inputs to several basal ganglia structures, using subthalamic
glutamic acid decarboxylase gene therapy is currently in Phase I trials. Neurotrophic
factors such as glial cell line-derived neurotrophic factor (GDNF) which support
survival, growth, and development of brain cells, have been shown to protect
dopamine neurons and even reverse the degeneration of nigrostriatal neurons in
animal models of PD. This drug has been tested in several clinical trials, and
appeared to cause regrowth of dopamine nerve fibres in one person who received the
drug. However, a phase II clinical study of GDNF was halted in 2004 because the
treatment did not show any clinical benefit after 6 months, and some data suggested
that it might be harmful. 2 Other neurotrophics, such as neurotrophin-4 (NT-4), brainderived neurotrophic factor (BDNF), and fibroblast growth factor 2 (FGF-2) are
under investigation, along with novel delivery methods of administration, including
direct delivery via infusions into the basal ganglia and the use of viral vectors; thus
far, these approaches have shown promising results.
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Replacing and Rebuilding?
Another approach to treating PD is to implant cells to replace those lost through the
disease. Researchers are conducting clinical trials of a cell therapy in which human
retinal epithelial cells attached to microscopic gelatine beads are implanted into the
brains of people with advanced PD. The retinal epithelial cells produce levodopa.
The investigators hope that this therapy will enhance brain levels of dopamine.
Starting in the 1990s, researchers conducted a controlled clinical trial to replace lost
dopamine-producing neurons with healthy ones from foetal tissue in order to improve
movement and the response to medications.5 While many of the implanted cells
survived and produced dopamine, this therapy gave only modest functional
improvements, mostly in patients under the age of 60. Unfortunately, some of the
people who received the transplants developed disabling dyskinesias that could not be
relieved by reducing antiparkinsonian medications.
Another type of cell therapy involves stem cells. Stem cells derived from embryos
can develop into any kind of cell in the body, while others, called progenitor cells, are
more restricted. One study transplanted neural progenitor cells derived from human
embryonic stem cells into a rat model of PD. The cells appeared to trigger
improvement on several behavioural tests, although relatively few of the transplanted
cells became dopamine-producing neurons. Researchers are now developing methods
to improve the number of dopamine-producing cells that can be grown from
embryonic stem cells in culture.
Researchers are also exploring whether stem cells from adult brains might be useful
in treating PD. They have shown that the brain's white matter contains multipotent
progenitor cells that can multiply and form all the major cell types of the brain,
including neurons.
Non-dopaminergic strategies?
Novel symptomatic treatments target nondopaminergic areas in the hope of avoiding
the motor complications seen with conventional therapies. Two emerging treatment
approaches under investigation6 are adenosine A(2a) receptor antagonists (such as
istradefylline) and glutamate AMPA receptor antagonists (such as talampanel).
A2a receptors are localised on medium spiny striatal neurons and modulate the
release of GABA. A2a antagonists also affect the release of acetylcholine from
striatal cholinergic interneurons and release dopamine from the nigrostriatal tract.
Such drugs may be important not only in controlling the symptoms of PD, but also in
preventing the wearing off seen with chronic treatment. In 2003, the publication of
results from two studies using istradefylline in patients with Parkinson's disease
showed a positive benefit of the study drug when used as adjunctive therapy to
levodopa. 7
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In non-human primate models of Parkinson's disease, talampanel has been found to
have antiparkinsonian effects when administered as high-dose monotherapy and
antidyskinetic effects on levodopa-induced dyskinesias.
Recent studies have shown that people with PD also have loss of noradrenalineproducing neurons. Noradrenaline, which is closely related to dopamine, is the main
chemical messenger of the sympathetic nervous system that controls many automatic
functions of the body, such as pulse and blood pressure. The loss of noradrenaline
might help explain several of the non-motor features seen in PD, including fatigue
and abnormalities of blood pressure regulation.
Other studies are looking at treatments that might improve some of the secondary
symptoms of PD, such as depression and swallowing disorders. One clinical trial is
investigating whether the anti-psychotic quetiapine can reduce psychosis or agitation
in PD patients with dementia and in dementia patients with parkinsonian symptoms.
Some studies also are examining whether transcranial magnetic stimulation can
alleviate depression in people with PD, and whether the anti-epileptic levetiracetam
can reduce dyskinesias in Parkinson's patients without interfering with other PD
drugs.
Surgical Stimulation
Reversible lesions of the subthalamic nucleus by deep brain stimulation (DBS) using
bilaterally implanted electrodes have dramatically improved signs and symptoms of
PD enabling patients to reduce their levodopa dose radically. 8 While DBS has now
been used in thousands of people with PD, researchers continue to try to improve the
technology and surgical techniques in this therapy. However, the procedure will
probably remain limited to specialist centres, and appropriate patient selection is
crucial to its successful use. Primate research also continues to show new roles in PD
for other brain structures outside the basal ganglia, like the pedunclopontine nucleus.9
Current studies are comparing DBS to the best medical therapy and trying to
determine which part of the brain is the best location for stimulation. These findings
provide exciting potential new targets for improving DBS.
Conclusions
While the ultimate goal of preventing PD may take years to achieve, researchers are
making great progress in understanding and treating PD. With so many therapies
currently under investigation, the time is ripe for the beginning of a new phase of
treatment strategies. How many of these will be commonplace by 2020 is not yet
known, but it seems likely that a balance between better pharmacological treatments
and surgical techniques will be guided by advances in neurophysiology, genetics and
clinical research. Until then, optimising treatment will likely include the use of
controlled-release formulas of current PD drugs and implantable continuous pumps.
Scientific progress is incremental and it seems unlikely that a disease first described
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nearly 200 years ago will be cured within a mere 12 years, but with the range of
exciting advances and potential therapies, this is a time for optimism for the future of
PD.
References
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