Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

Carlsson, Thomas; Carta, Manolo; Winkler, Christian; Björklund, Anders; Kirik, Deniz

doi:10.1523/jneurosci.2079-07.2007

Cited by 176 publications

(127 citation statements)

References 40 publications

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“…For example, the A9 DA neurons have a better capacity to control the physiological release and synaptic availability of DA than the ventral tegmental area (VTA) A10 neurons because of the higher presynaptic DA autoreceptor and DA transporter levels that occur in A9 DA neurons [14,15]. Furthermore, the presence of non-DA neurons, such as serotoninergic neurons, has recently been implicated in the evolution of dyskinesias in animal studies [5,6]. We feel that stem cell technology will provide a more uniform and desirable cell source than fetal cells for clinical transplantation.…”

Section: Cell Preparation Techniques and Patient Recipient Status Maymentioning

confidence: 99%

Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients

et al. 2009

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Postmortem analyses from clinical neural transplantation trials of several subjects with Parkinson's disease revealed surviving grafted dopaminergic neurons after more than a decade. A subset of these subjects displayed isolated dopaminergic neurons within the grafts that contained Lewy body-like structures. In this review, we discuss why this isolated cell damage is unlikely to affect the overall graft function and how we can use these observations to help us to understand age-related neurodegeneration and refine our future cell replacement therapies.

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Section: Cell Preparation Techniques and Patient Recipient Status Maymentioning

confidence: 99%

Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients

et al. 2009

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“…With the landmarks commonly used for dissection of the fetal tissue, the number of serotonin neurons is likely to be quite large, probably in the order of half of the DA neurons present in these preparations. Experiments in the rat 6-hydroxydopamine model suggest that serotonin neurons can exacerbate dyskinesia induced by L-DOPA, and we have proposed that the presence of large numbers of serotonin neurons in the grafts, in combination with a suboptimal number of DA neurons could make grafted patients more prone to develop GID [44].…”

Section: Adverse Effects Are Few With Dopaminergic Grafts Except Dysmentioning

confidence: 99%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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“…Blunting the efflux of dopamine, by a 5-HT-specific lesion, dramatically reduces the severity of LID [6]. In contrast, enhancing the striatal 5-HT fibre outgrowth in the dopamine-denervated striatum, by a 5-HT neuronal transplant, exacerbates LID [10].…”

Section: Serotonin's Multiple Mechanisms Of Actions In the Basal Gangliamentioning

confidence: 99%

2.12.2 the Serotonin System: A Potential Target for Anti-Dyskinetic Treatments and Biomarker Discovery

Rylander¹

2012

Parkinsonism & Related Disorders

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L-DOPA-induced dyskinesia is a major problem in the treatment of Parkinson's disease. Today there are few anti-dyskinetic treatments available for the patients, and all of them have major limitations.Recent findings have revealed an important role of the serotonin system in L-DOPA-induced dyskinesia. In the parkinsonian brain, serotonin axon terminals can compensate for the dopamine loss by converting L-DOPA into dopamine and releasing it as a false neurotransmitter. However, the terminals represent an aberrant source of dopamine release, increasing the risk for dyskinesia. In line with this, a relatively high density of serotonin axon fibres in striatum has been reported in dyskinetic animals and patients. Furthermore, serotonin can influence dyskinesia by modulating glutamate or GABA signalling in the basal ganglia via receptors located on non-serotonergic neurons. Through either mechanism, modulation of certain serotonin receptors has shown to reduce the severity of dyskinetic movements.The serotonin system represents an interesting target for developing antidyskinetic treatments. Future therapies may take advantage of the synergistic effect produced by the modulation of different serotonin receptors or pursue a region-specific modulation of certain receptors. Moreover, morphological or biochemical features of the serotonin system could be used to develop biomarkers for patient stratification in clinical trials of anti-dyskinetic compounds.

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Serotonin Neuron Transplants Exacerbate l-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease

Abstract: Clinical trials in patients with

Cited by 176 publications

References 40 publications

Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients

Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients

Cell Therapeutics in Parkinson's Disease

2.12.2 the Serotonin System: A Potential Target for Anti-Dyskinetic Treatments and Biomarker Discovery

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