Parkinson's Researchers Pumped by Trial; L-DOPA Makes Synapses Hyperactive
In today's Nature journals online, two articles provide new insights and new hope for the treatment of Parkinson's disease.
In Nature Medicine, a collaboration led by Peter Heywood at Frenchay Hospital, Bristol, UK, and Clive Svendsen at the University of Wisconsin, Madison, reports the results of a clinical trial for glial cell line-derived neurotrophic factor (GDNF), a potent peptide hormone with neuroprotective and nerve growth stimulatory properties. GDNF has been used recently to treat PD patients (see Nutt et al. 2003) without much success. But now, first author Steven Gill and colleagues show that it can lead to substantial improvements in motor skills and a reduction in involuntary muscle movements, or dyskinesia, associated with the PD medication L-DOPA.
The reason for this success appears to lie in the mode of administration. Gill and colleagues delivered the protein directly to the putamen-the part of the Parkinson’s brain most deprived of the neurotransmitter dopamine-whereas previous attempts had placed the GDNF in the cerebral ventricles, or cavities, from where it had to diffuse to the site of action. Gill and colleagues also used small pumps to supply a continuous stream of the factor via a permanently installed catheter, in contrast to previous methods that relied on passive diffusion from an injected bolus of the protein.
In this trial, five patients were enrolled and treated for over 18 months. All showed substantial improvement in a battery of tests. On average, the Unified Parkinson's Disease Rating Scale (UPDRS), a standard test to measure advancement of the disease, was only about half that recorded before treatment started. In addition, episodes of dyskinesia, occurring when patients are off medication, were eliminated in all five volunteers, and they also took less time to perform motor tests (up to 60 percent shorter). Gill and colleagues recorded the improvements after three months of therapy and, except for one patient, the volunteers continued to improve slightly over the next nine months.
To assess any improvement at the physiological level, the authors used PET scans of dopa uptake, which gives an indication of the dopamine storage capacity of the brain and hence the condition of dopaminergic neurons. After 18 months of GDNF treatment, dopa uptake capacity had increased by an average of almost 30 percent in the region immediately surrounding the catheter, whereas the capacity in regions distal to the catheters continued to decline.
A full phase 2 trial is now required to assess the value of this treatment, yet these initial results are encouraging. Very few side effects were observed.
In Nature Neuroscience, another multinational group, headed by Paolo Calabresi at the University of Rome, reports that L-DOPA-induced dyskinesia is associated with changes in synaptic plasticity, or the ability of neurons to change synaptic connections in response to stimuli. Synaptic plasticity is associated with learning, and researchers have long thought that dyskinesia reflects some motor learning process gone awry.
First author Barbara Picconi and colleagues addressed this concept using a rat model of Parkinson's disease. They administered low doses of L-DOPA to these animals and found that some of them do not have any involuntary muscle movement. To explain this observation, the authors examined the plasticity of striatal neurons, which are thought to be responsible for the dyskinesia.
One suspected underlying mechanism of plasticity is a behavior called long-term potentiation, or LTP, which is easily measured by electrophysiology. Neurons respond to repeated rapid stimuli by increasing the strength of their own outputs. When Picconi and colleagues exposed striatal neurons from dyskinetic rats to high-frequency stimulation, the cells responded with stronger outputs of their own, just like neurons from control and nondyskinetic rats. However, when the authors tried depotentiation, they found that neurons from dyskinetic and nondyskinetic animals behaved differently.
Depotentiation is like LTP in reverse. After a neuron has responded to rapid stimuli by increasing the amplitude of its own output, it can be coaxed back to its normal state by very low-frequency stimuli. Picconi found this type of plasticity in neurons from normal and nondyskinetic rats, but the neurons from the dyskinetic rats failed to settle back to their normal state, instead remaining "hyperactive."
At the molecular level, the authors found a link between this "hyperactivity" and modification of proteins by addition of phosphate moieties. Phosphates can only be removed by a group of enzymes called protein phosphatases. When Picconi added protein phosphatase inhibitors to normal striatal neurons, depotentiation was blocked, just as in the dyskinetic neurons. Furthermore, in the putamen of dyskinetic rats, the authors found levels of phosphorylated DARPP-32, a potent inhibitor of protein phosphatase 1, to be almost twice that of normal and nondyskinetic rats.
The authors write that this loss of bidirectional plasticity may lead to the development of abnormal motor patterns, and that "strategies aimed at restoring this plasticity may represent an alternative approach to prevent and/or treat motor abnormalities in PD patients." In this regard, it is worth noting that stimulation of dopamine D1 receptors activates the phosphorylation of DARPP-32, while patients treated with dopamine D2 agonists develop less dyskinesia than those treated with L-DOPA, which binds to both D1 and D2 receptors (see Jankovic, 2002 and ARF related news story).—Tom Fagan
- Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER, Lozano AM, Penn RD, Simpson RK, Stacy M, Wooten GF, . Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 2003 Jan 14;60(1):69-73. PubMed.
- Blakeley J, Jankovic J. Secondary causes of paroxysmal dyskinesia. Adv Neurol. 2002;89:401-20. PubMed.
No Available Further Reading
- Gill SS, Patel NK, Hotton GR, O'Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003 May;9(5):589-95. PubMed.
- Picconi B, Centonze D, Håkansson K, Bernardi G, Greengard P, Fisone G, Cenci MA, Calabresi P. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci. 2003 May;6(5):501-6. PubMed.
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University of Pittsburgh
These papers provide support for Parkinson's disease therapies and a basis for understanding L-DOPA's iatrogenic effects. It is curious that the GDNF recovery of function proceeded even as brain deterioration progressed.
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