| 1. |
- Lindgren, Hanna, et al.
(author)
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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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In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X .- 0893-133X. ; 34, s. 2477-2488
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Journal article (peer-reviewed)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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| 2. |
- Lindgren, Hanna, et al.
(author)
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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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In: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 177:1, s. 150-159
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Journal article (peer-reviewed)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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| 3. |
- Ohlin, Elisabet, et al.
(author)
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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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In: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 134, s. 2339-2357
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Journal article (peer-reviewed)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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