| 1. |
- 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. |
- Cenci Nilsson, Angela, et al.
(författare)
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Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia.
- 2009
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Ingår i: Parkinsonism & Related Disorders. - 1873-5126. ; 15 Suppl 3, s. 59-63
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Tidskriftsartikel (refereegranskat)abstract
- The development of L-DOPA-induced dyskinesia (LID) is attributed to plastic responses triggered by dopamine (DA) receptor stimulation in the parkinsonian brain. This article reviews studies that have uncovered different levels of maladaptive plasticity in animal models of LID. Rats developing dyskinesia on chronic L-DOPA treatment show abnormal patterns of signaling pathway activation and synaptic plasticity in striatal neurons. In addition, these animals show a gene expression profile indicative of structural cellular plasticity, including pronounced upregulation of genes involved in extracellular matrix remodeling, neurite extension, synaptic vesicle trafficking, and endothelial and cellular proliferation. Structural changes of neurons and microvessels within the basal ganglia are currently being unraveled by detailed morphological analyses. The structural and functional adaptations induced by L-DOPA in the brain can be viewed as an attempt to meet increased metabolic demands and to boost cellular defense mechanisms. These homeostatic responses, however, also predispose to the appearance of dyskinesia and other complications during the course of the treatment.
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| 3. |
- Cenci Nilsson, Angela, et al.
(författare)
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Rodent models of treatment-induced motor complications in Parkinson's disease
- 2009
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Ingår i: Parkinsonism and Related Disorders. - 1873-5126. ; 15 Suppl 4, s. 7-13
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Tidskriftsartikel (refereegranskat)abstract
- Treatment-induced motor complications represent a major clinical problem in Parkinson's disease (PD). Pharmacological dopamine (DA) replacement with l-dopa causes motor fluctuations and abnormal involuntary movements (dyskinesia) in the vast majority of the patients. Intrastriatal grafts of embryonic dopaminergic neurons can cause dyskinesia too, as shown by clinical trials of neural transplantation in PD. Animals models of these complications can be produced in rats and mice in which the nigrostriatal DA pathway has been severely damaged. Rodent models allow investigators to explore mechanistic hypotheses at the cellular and molecular level. Moreover, the rat model of L-dopa-induced abnormal involuntary movements shows both face validity and predictive validity relative to the corresponding disorder in primates, and provides a cost effective tool to evaluate novel antidyskinetic interventions. This article reviews the strategies that have been used to reproduce different motor complications of PD treatment in rodents, and comments on their range of applicability.
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| 4. |
- Grauers, Anna, et al.
(författare)
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Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis
- 2015
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Ingår i: The Spine Journal. - Stockholm : Karolinska Institutet, Dept of Clinical Science, Intervention and Technology. - 1529-9430 .- 1878-1632.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. Purpose: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. Study design: This was a case control study. Patient sample: A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. Outcome measure: The outcome measure was idiopathic scoliosis. Methods: The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5′UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. Results: Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10−18). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5′UTR, noncoding exon and promoter regions of LBX1. Conclusions: Here, we confirm LBX1 as a susceptibility gene for idiopathic scoliosis in a Scandinavian population and report that we are unable to find evidence of other genes of similar or stronger effect.
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| 5. |
- Lindgren, Hanna, et al.
(författare)
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Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease.
- 2009
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X .- 0893-133X. ; 34, s. 2477-2488
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1- or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1- but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.Neuropsychopharmacology advance online publication, 15 July 2009; doi:10.1038/npp.2009.74.
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| 6. |
- Lindgren, Hanna, et al.
(författare)
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The "motor complication syndrome" in rats with 6-OHDA lesions treated chronically with l-DOPA: Relation to dose and route of administration.
- 2007
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 177:1, s. 150-159
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Tidskriftsartikel (refereegranskat)abstract
- l-DOPA-induced motor complications can be modelled in rats with 6-hydroxydopamine (6-OHDA) lesions by chronic injections of l-DOPA. We have compared the sensitisation and duration of rotational responses, and the occurrence of dose–failure episodes and abnormal involuntary movements (AIMs) in 6-OHDA-lesioned rats with regard to the dose and route of administration of l-DOPA. Rats were treated with either low (6 mg/kg) or high (25 mg/kg) doses of l-DOPA twice daily for 21 days whereas control animals received injections of either saline or bromocriptine (2.5 mg/kg). A dose-dependent and gradual development of AIMs and contralateral turning was observed in rats treated chronically with l-DOPA. Rats treated with bromocriptine exhibited rotational sensitisation but no AIMs. A shortening of motor response duration was not seen in any of the drug-treated groups. In contrast, dose–failure episodes occurred frequently in both l-DOPA- and bromocriptine-treated animals. Changing the route of l-DOPA administration from intraperitoneal to subcutaneous completely abolished failures in motor response without affecting the development of dyskinesia. Based on the hypothesis that higher doses of l-DOPA may be toxic to dopaminoceptive structures, we compared the total number of neurons and the levels of activated microglia in the striatum. No signs of neurodegenerative changes could be seen in any of the treatment groups. In conclusion, both body AIMs and rotations were dose-dependently evoked by l-DOPA. Only AIMs, however, provided a specific measure of dyskinesia since rotations also were induced by bromocriptine, a drug with low dyskinesiogenic potential. Dose–failure episodes were not specific to l-DOPA treatment and could be attributed to erratic drug absorption from the peritoneal route.
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| 7. |
- 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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| 8. |
- 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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| 9. |
- 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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| 10. |
- Persson Skare, Tor, et al.
(författare)
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Novel anti-VEGF therapeutics
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Excessive and chronic vascular leakage in pathologies such as eye diseases leads to edema, tissue ischemia and disease progression. To suppress vascular leakage by blocking vascular endothelial growth factor (VEGF) function is clinically beneficial. However, development of new, topically applied therapeutic options is important as intravitreal injections currently carried out to deliver anti-VEGF therapeutics is expensive and may have serious side effects. VEGF receptor-2 (VEGFR2) activates Src family kinases via binding the T cell specific adaptor (TSAd) to its phosphotyrosine residue Y951. These molecular interactions are required for gap formation at endothelial junctions and vascular leakage. Here, we describe the identification from a high throughput screen, of a small molecular weight inhibitor (LC1) which blocks the interaction between the phosphorylated VEGFR2 kinase domain and TSAd. LC1 binds to TSAd in surface plasmon resonance analysis. In intact cells, LC1 suppresses VEGFR2 kinase activity while if fails to inhibit kinase activity in an in vitro biochemical kinase screen of 35 kinases including VEGFR2. Superfusion of retinal explants blocks vascular leakage from retinal vessels. In conclusion, we have identified a compound which specifically blocks VEGFR2 function in endothelial cells.
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