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- Cenci Nilsson, Angela, et al.
(författare)
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Current Options and Future Possibilities for the Treatment of Dyskinesia and Motor Fluctuations in Parkinson's Disease
- 2011
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Ingår i: CNS and Neurological Disorders - Drug Targets. - : Bentham Science Publishers Ltd.. - 1871-5273. ; 10:6, s. 670-684
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Tidskriftsartikel (refereegranskat)abstract
- Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.
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| 2. |
- Ohlin, Elisabet, et al.
(författare)
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Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson's disease.
- 2012
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Ingår i: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 61:1, s. 228-239
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Tidskriftsartikel (refereegranskat)abstract
- Large increases in regional cerebral blood flow (rCBF) have been measured in patients with Parkinson's disease (PD) following the administration of L-DOPA, but the underlying mechanisms have remained unknown. In this study, we have used rats with unilateral 6-hydroxydopamine (6-OHDA) lesions as a model of PD in order to compare the patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated 6-OHDA-lesioned and sham-lesioned rats following a final injection of L-DOPA or saline. In the same animal model, we have compared the leakage of a blood-brain barrier (BBB) tracer molecule at 60min vs. 24h following the last L-DOPA injection of a chronic treatment. All the parameters under investigation were examined with brain autoradiography following intravenous injections of specific radiotracers in awake animals ([14C]-iodoantipyrine for rCBF, [14C]-2-deoxyglucose for rCGU, and [14C]-α-aminoisobutyric acid for BBB leakage). Significant changes in rCBF and rCGU on the side ipsilateral to the 6-OHDA lesion relative to the non-lesioned side were seen at 60min ("ON") but not 24h ("OFF") following L-DOPA administration. These changes were not seen in sham-operated rats. In the output nuclei of the basal ganglia (the entopeduncular nucleus and the substantia nigra pars reticulata) both rCBF and rCGU were elevated both in acutely L-DOPA-treated rats and chronically L-DOPA-treated rats displaying dyskinesia, but did not change significantly in chronically L-DOPA-treated non-dyskinetic cases. Acutely and chronically L-DOPA-treated rats with dyskinesia exhibited increases in rCBF "ON L-DOPA" also in the motor cortex, the striatum, and the globus pallidus, but the corresponding changes in rCGU did not show the same direction, magnitude, and/or relative group differences. The uptake of a BBB tracer (studied in the striatum and the substantia nigra reticulata in chronically L-DOPA treated rats) was significantly higher ON vs. OFF L-DOPA. The present results are the first to show that the administration of L-DOPA is followed by transient and robust increases in rCBF in the dopamined enervated basal ganglia networks. This effect occurs already upon acute L-DOPA treatment and persists upon repeated drug administration in animals that develop dyskinesia. Increases in rCBF ON L-DOPA are not necessarily accompanied by enhanced glucose utilisation in the affected regions, pointing to altered mechanisms of neurovascular coupling. Finally, our results show that increases in rCBF ON L-DOPA may be accompanied by BBB hyperpermeability in the most affected regions.
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| 3. |
- Ohlin, Elisabet
(författare)
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Microvascular plasticity and neurovascular coupling in the pharmacotherapy of Parkinson's disease
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- L-DOPA pharmacotherapy in Parkinson’s disease (PD) is associated with adverse effects occurring after a few years of treatment. Among these, dyskinesia (abnormal involuntary movements) is particularly common and potentially disabling. The causes behind dyskinesia are not completely understood, but intense research has identified a number of neuronal alterations associated with L-DOPA-induced dyskinesia in both PD patients and animal models of PD. In addition to neurons, the brain consists of a dense vascular network and supportive cells. This thesis has focused on non-neuronal aspects contributing to the pathophysiology of dyskinesia. In particular, it has addressed structural and functional changes affecting the microvasculature in the basal ganglia. Using rats with unilateral 6-hydroxydopamine (6-OHDA) lesions as an animal model of PD, the first paper of this thesis demonstrates that dyskinesia induced by either direct dopamine D1 agonism or L-DOPA, are indistinguishable at the level of angiogenic activity in the basal ganglia. Endothelial proliferation, nestin upregulation and downregulation of blood-brain barrier indices, were equally present in both D1- or L-DOPA-induced dyskinetic rats. Moreover, concomitant D1 stimulation by L-DOPA and a D2 antagonist, potentiated the angiogenic response without affecting the severity of dyskinesia. The second paper of this thesis shows that indices of angiogenesis and the expression of vascular endothelial growth factor (VEGF) are dose-dependently upregulated in the striatum and the substantia nigra pars reticulata following chronic L-DOPA treatment. Interestingly, VEGF immunoreactivity was mainly expressed in astrocytes in proximity to blood vessels. Induction of VEGF mRNA was seen in rat primary astrocytic cultures following incubation with D1 receptor stimulation. To verify the causal involvement of VEGF in the development of dyskinesia, 6-OHDA-lesioned rats were chronically co-treated with L-DOPA along with an inhibitor of VEGF receptor-signalling (vandetanib). Rats receiving vandetanib co-treatment, but not its vehicle, developed less severe dyskinesia and did not show a significant angiogenic response to L-DOPA. The occurrence of angiogenesis was investigated also on post mortem basal ganglia sections from PD patients. Histological indices of angiogenesis (i.e. the density of CD34- and nestin-immunopositive microvessels) were significantly higher in dyskinetic PD patients compared to non-dyskinetic PD cases and neurologically healthy controls. Striatal tissue samples from a separate set of dyskinetic patients showed a significant upregulation of VEGF mRNA. Prompted by the hypothesis that L-DOPA-induced angiogenesis may be accompanied by changes in regional cerebral blood flow (rCBF) in the affected regions, we carried out an extensive comparison of changes in rCBF and regional cerebral glucose utilization (rCGU) in unilaterally 6-OHDA-lesioned rats both at baseline and following the administration of L-DOPA (third article in the thesis). The results of this study demonstrate robust increases in rCBF at 60 minutes following the administration of L-DOPA (“ON L-DOPA”) in the same basal ganglia nuclei that show angiogenic activity upon chronic L-DOPA treatment. The rCBF response was not always paralleled by an increase in rCGU, pointing to a direct haemodynamic effect of the treatment. By comparing the passage of a tracer molecule across the blood-brain barrier in chronically L-DOPA-treated rats, we could finally show a significantly larger accumulation of the tracer in the striatum and the substantia nigra pars reticulata at 60 minutes (“ON”) compared to 24 hours (“OFF”) following the last peripheral L-DOPA injection. In conclusion, this thesis provides evidence that dopamine replacement therapy for PD does not only affect neurons, but that important plastic changes occur at the level of the microvasculature in the basal ganglia. These changes are tightly linked to the development of a dyskinetic motor response. On the basis of these findings, it is recommended that future therapeutic initiatives for PD also consider targets that are expressed in the microvasculature and/or neurovascular coupling mechanisms that are specific to the parkinsonian brain.
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| 4. |
- Ohlin, Elisabet, et al.
(författare)
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Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.
- 2011
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 134, s. 2339-2357
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.
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