Mr J.McGrath, 2008 1/5
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. 3This 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 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 inflammation-promoting 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), brain-derived 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.
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
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 noradrenaline-producing 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 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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3. NINDS. "Parkinson's Disease: Hope Through Research" 2006; NIH Publication No. 06-139.
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