Abstract
One of the major symptoms of the neurodegenerative condition Parkinson’s disease (PD) is a slowness or loss of voluntary movement, yet frustratingly therapeutic strategies designed to restore movement can result in the development of excessive abnormal movements known as dyskinesia. These dyskinesias commonly develop as a result of pharmacotherapy in the form of L-DOPA administration, but have also been identified following deep brain stimulation (DBS) and intrastriatal cell transplantation. In the case of L-DOPA these movements can be treatment limiting, and whilst they are not long lasting or troubling following DBS, recognition of their development had a near devastating effect on the field of cell transplantation for PD.Understanding the relationship between these therapeutic approaches and the development of dyskinesia may improve our ability to restore function without disabling side effects. Interestingly, despite the fact that dopaminergic cell transplantation repairs many of the changes induced by the disease process and through L-DOPA treatment, there appears to be a relationship between the two. In rodent models of the disease, the severity of dyskinesia induced by L-DOPA prior to the transplantation procedure correlated with post-transplantation, graft-induced dyskinesia. A review of clinical data also suggested that the worse preoperational dyskinesia causes worsened graft-induced dyskinesia (GID). Understanding how these aberrant behaviors come about has been of keen interest to open up these therapeutic options more widely and one major underlying theory is the effects of these approaches on the plasticity of synapses within the basal ganglia. This review uniquely brings together developments in understanding the role of striatal synaptic plasticity in both L-DOPA and GID to guide and stimulate further investigations on the important striatal plasticity.
Highlights
Parkinson’s disease (PD) is a degenerative disease typically associated with aging
We do note here though that there is some controversy over the exact implication of the presence of Lewy bodies in the disease, as some unusual forms of PD present without Lewy body pathology and in contrast incidental Lewy body disease is defined as the presence of Lewy bodies without clinical signs of PD
This review focuses on the role that striatal synaptic plasticity may play in the development of dyskinesia following both L-DOPA administration and cell transplantation
Summary
Parkinson’s disease (PD) is a degenerative disease typically associated with aging. previously considered a pure motor disorder, it is widely recognized that the disease presents with the classically described motor impairments such as tremor, akinesia, postural instability and rigidity, but in addition most patients suffer from a range of non-motor symptoms that can include depression, constipation, dysasthesia and in the later stages for many patients, dementia (Juri et al, 2008). Two main types of LID are described, the first, and best characterized being ‘‘peak dose dyskinesia’’; monophasic, typically choreiform in nature, purposeless and non-rhythmic and often affecting the more severely parkinsonian side of the body to a greater extent They appear as the plasma L-DOPA levels peak and are sustained until they decrease, typically covering much of the effective period of the drug (2–3 h). One significant surgical intervention, which has become used world-wide over the last 15 years, is deep brain stimulation (DBS) in which electrodes delivering high frequency stimulation are implanted bilaterally into the subthalamic nucleus This has the immediate effect of reducing motor symptoms and alleviating the need for high dose L-DOPA therapy and many patients are able to reduce their medication significantly once the stimulators are turned on, and their LID. Taking into account some implicit reports of aberrant movements post transplantation (reviewed in Lane et al, 2010) this average across six trials is still 32% of patients and demonstrates a significant concern in the development of transplantation as a reliable and safe therapy for PD
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