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| 2. |
- Cenci Nilsson, Angela, et al.
(författare)
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Dyskinesias and neural grafting in Parkinson's disease
- 2006
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Ingår i: Restorative Therapies in Parkinson's Disease. - : Springer US. - 9780387299846 - 9780387328232 ; , s. 184-224
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Bokkapitel (populärvet., debatt m.m.)abstract
- In the past 20 years, intracerebral transplantation of embryonic ventral mesencephalic (VM) tissue has been looked upon as a particularly promising approach for the treatment of Parkinson's disease (PD). Among the many possible treatment options for the future, transplantation bore the promise of a truly curative approach: endogeneous, degenerating dopamine (DA) neurons would be substituted for by healthy DA-producing cells, restoring the damaged nigrostriatal circuit once and for all (Nikkhah and Brandis, 1995; Barker, 2000; Fricker-Gates et al., 2001). Hopes were fostered by the encouraging results produced by intrastriatal VM transplants both in animal models of PD (Bj?rklund, 1992; Bj?rklund and Stenevi, 1979; Herman and Abrous, 1994; Perlow et al., 1979) and in early openlabel clinical trials (Lindvall, 1994; Lindvall and Hagell, 2000 and Chapter 5). The latter showed that embryonic VM tissue can engraft in the parkinsonian striatum and provide a local source of DA storage and release. In a majority of transplanted patients the grafts were found to ameliorate many of the symptoms of PD and to reduce the need for L-DOPA pharmacotherapy (Lindvall and Hagell, 2000). In addition to their immediate implications for PD, these results also suggested that neural cell replacement could develop into a radically new treatment approach for a wide range of neurological disorders (Gage et al., 1988; Lindvall and Bj?rklund, 1992; Aichner et al., 2002; Turner and Shetty, 2003; Grisolia, 2002; Peschansky and Dunnett, 2002; Studer et al., 1998). This early enthusiasm was dampened by alarming reports from the first NIH-sponsored clinical trial of neural transplantation, where a subgroup of patients had manifested a severe and persistent form of dyskinesia at late postoperative periods (Freed et al., 2001; Greene et al., 1999; Kolata, 2001 and Chapter 6). Other reports were soon to follow indicating that dyskinesias indeed can develop as a complication of intrastriatal VM grafting (Hagell et al., 2002; Ma et al., 2002; Olanow et al., 2003). These dyskinesias are a puzzling phenomenon that had not been foreseen by experimental studies of VM transplantation in animal models. This phenomenon does not presently lend itself to any simple explanation. In fact, current pathophysiological models are inadequate to explain the emergence of dyskinesia after interventions that can provide a source of continuous DA release in the striatum. Yet, understanding this issue appears essential in order to be able to plan further application of cell-replacement therapy in PD. In this chapter, we shall first provide a general review of the clinical spectrum and pathophysiology of the dyskinesias that complicate the treatment of PD. We shall then discuss the effects of VM grafts on L-DOPA-induced dyskinesias that are present prior to transplantation surgery. Thereafter, we will specifically address the issue of graft-induced dyskinesia, viz., an apparently novel clinical entity that is caused by the intrastriatal grafts themselves. Finally, we shall provide a speculative review of possible mechanisms underlying the development of dyskinesia following intrastriatal VM transplantation.
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| 3. |
- Lane, Emma, et al.
(författare)
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Amphetamine-induced abnormal movements occur independently of both transplant- and host-derived serotonin innervation following neural grafting in a rat model of Parkinson's disease.
- 2009
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 35, s. 42-51
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin has been postulated to play a role in the transplant-induced involuntary movements that occur following intrastriatal grafts of ventral mesencephalic tissue in the treatment of Parkinson's disease. Serotonin innervation of the striatum may be derived from either the donor graft tissue or the normal host projections from the midbrain. In two sets of experiments we study the impact of graft- versus host-derived serotonin innervation. All experiments were performed in l-DOPA treated rats with unilateral 6-hydroxydopamine lesions. As expected, following intrastriatal transplantation of embryonic ventral mesencephalon all the transplanted rats exhibited pronounced contralateral rotation in response to amphetamine and some animals also showed severe abnormal involuntary movements (AIMs). In the first set of experiments, all types of AIMs (axial, limb, orolingual and locomotor) were markedly reduced when amphetamine was co-administered with either the D(2) dopamine receptor antagonist raclopride or the D(1) receptor antagonist SCH23390. Cotreatment with the 5-HT(1A) agonist 8-OH-DPAT significantly attenuated the amphetamine-induced axial and limb dyskinesias, whilst locomotor scores remained unchanged. These data point to a major role for dopamine receptors, and to a modulatory role for 5-HT(1A) receptors, in post-grafting dyskinesias. In the second experiment, grafted rats exhibiting amphetamine-induced dyskinesia were subjected to 5,7-dihydroxytryptamine injections into the midbrain in order to destroy the host serotonin innervation. This intervention had no effect on either amphetamine-induced AIMs or contralateral rotation. Histological examination of all grafted rats showed similar numbers of dopaminergic neurons and a very low number of serotonin neurons within the transplants, regardless of AIMs expression. Our results suggest that amphetamine-induced AIMs in grafted animals primarily depend on an activation of dopamine receptors, and that serotonin neurons within either the grafts or the host brain play a negligible role.
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| 4. |
- Lane, Emma, et al.
(författare)
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Neuroinflammation in the generation of post-transplantation dyskinesia in Parkinson's disease.
- 2008
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 32, s. 220-228
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Tidskriftsartikel (refereegranskat)abstract
- The observation that neural grafts can induce dyskinesias has severely hindered the development of a transplantation therapy for Parkinson's disease (PD). We addressed the hypothesis that inflammatory responses within and around an intrastriatal graft containing dopamine neurons can trigger dyskinetic behaviors. We subjected rats to unilateral nigrostriatal lesions with 6-hydroxydopamine (6-OHDA) and treated them with L-DOPA for 21 days in order to induce abnormal involuntary movements (AIMs). Subsequently, we grafted the rats with allogeneic embryonic ventral mesencephalic tissue in the dopamine-denervated striatum. In agreement with earlier studies, the grafted rats developed dyskinesia-like AIMs in response to amphetamine. We then used two experimental approaches to induce an inflammatory response and examined if the amphetamine-induced AIMs worsened or if spontaneous AIMs developed. In one experiment, we challenged the neural graft hosts immunologically with an orthotopic skin allograft of the same genetic origin as the intracerebral neural allograft. In another experiment, we infused the pro-inflammatory cytokine interleukin 2 (IL-2) adjacent to the intrastriatal grafts using osmotic minipumps. The skin allograft induced rapid rejection of the mesencephalic allografts, leading to disappearance of the amphetamine-induced AIMs. Contrary to our hypothesis, the rejection process itself did not elicit AIMs. Likewise, the IL-2 infusion did not induce spontaneous AIMs, nor did it alter L-DOPA-induced AIMs. The IL-2 infusions did, however, elicit the predicted marked striatal inflammation, as evidenced by the presence of activated microglia and IL2Ralpha-positive cells. These results indicate that an inflammatory response in and around grafted dopaminergic neurons is not sufficient to evoke dyskinetic behaviors in experimental models of PD.
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| 5. |
- Lane, Emma, et al.
(författare)
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Priming for L-DOPA-induced abnormal involuntary movements increases the severity of amphetamine-induced dyskinesia in grafted rats.
- 2009
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 219, s. 355-358
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Tidskriftsartikel (refereegranskat)abstract
- In some patients, graft-induced dyskinesia develops following intrastriatal transplantation of embryonic neural tissue for the treatment of Parkinson's disease. The mechanisms underlying these involuntary movements need to be clarified before this approach to clinical cell therapy can be developed further. We previously found that rats with 6-OHDA lesions, primed with L-DOPA treatment and that have subsequently undergone intrastriatal graft surgery exhibit involuntary movements when subjected to amphetamine. This model of amphetamine-induced AIMs reflects a pattern of post-graft behaviors that in the absence of robust spontaneous GID in the rat is the closest approximation that we currently have available. We now show that they are associated with the chronic administration of L-DOPA prior to the transplantation surgery. We also demonstrate that neither changes in c-fos nor FosB/DeltaFosB expression in the lateral striatum are associated with the expression of these behaviours. Taken together, these data reveal that the severity of abnormal movements elicited by amphetamine in grafted animals may relate to previous L-DOPA exposure and dyskinesia development, but they develop through mechanisms that are independent of FosB/DeltaFosB upregulation.
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| 6. |
- Lane, Emma, et al.
(författare)
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The impact of graft size on the development of dyskinesia following intrastriatal grafting of embryonic dopamine neurons in the rat.
- 2006
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 22:2, s. 334-345
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Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal transplants of embryonic ventral mesencephalon can cause dyskinesia in patients with Parkinson's disease (PD). We assessed the impact of transplant size on the development of graft-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions were primed to exhibit l-DOPA-induced dyskinesia. They were then intrastriatally grafted with different quantities of embryonic ventral mesencephalic tissue to give small and large grafts. Without drug treatment, discrete dyskinetic-like movements were observed in most rats with large grafts 2–6 weeks after transplantation, but disappeared later. Amphetamine evoked severe abnormal involuntary movements (AIMs) in grafted animals, which were more striking with large grafts. The AIMs coincided with contralateral rotation, but displayed a different temporal profile and pharmacological properties. Thus, selective dopamine uptake blockade elicited rotational behavior, whereas coadministration of both dopamine and serotonin uptake blockers was required to evoke significant orolingual and limb AIMs. In conclusion, robust and reproducible AIMs were evoked in rats with large grafts by blockade of monoamine reuptake. These AIMs may provide a new tool for assessing dyskinetic effects of neural grafting.
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| 7. |
- Westin, Jenny, et al.
(författare)
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Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia.
- 2006
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Ingår i: JNeurosci. - 1529-2401. ; 26:37, s. 9448-9461
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Tidskriftsartikel (refereegranskat)abstract
- 3,4-Dihydroxyphenyl-(L)-alanine ((L)-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) concomitantly with (L)-DOPA for 2 weeks. A large number of BrdU-positive cells were found in the striatum and its output structures (globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata) in (L)-DOPA-treated rats that had developed dyskinesia. The vast majority (60-80%) of the newborn cells stained positively for endothelial markers. This endothelial proliferation was associated with an upregulation of immature endothelial markers (nestin) and a downregulation of endothelial barrier antigen on blood vessel walls. In addition, dyskinetic rats exhibited a significant increase in total blood vessel length and a visible extravasation of serum albumin in the two structures in which endothelial proliferation was most pronounced (substantia nigra pars reticulata and entopeduncular nucleus). The present study provides the first evidence of angiogenesis and blood-brain barrier dysfunction in an experimental model of (L)-DOPA-induced dyskinesia. These microvascular changes are likely to affect the kinetics of (L)-DOPA entry into the brain, favoring the occurrence of motor complications.
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