title: Angiotensin type 1 receptor blockage reduces l-dopa-induced dyskinesia in the 6-OHDA model of Parkinson's disease. Involvement of vascular endothelial growth factor and interleukin-1β.
abstract: Non-neuronal factors such as angiogenesis and neuroinflammation may play a role in l-dopa induced dyskinesias (LID). Vascular endothelial growth factor (VEGF) and proinflammatory cytokines such as interleukin-1β (IL-1β) have been found to be involved in LID. The renin-angiotensin system (RAS) is involved in the inflammatory response and VEGF synthesis via type 1 (AT1) receptors. However, it is not known whether the RAS plays a role in LID and whether AT1 antagonists could constitute a useful therapy against LID. In this study, we investigated whether manipulation of brain RAS is effective in preventing LID. Blocking AT1 receptors with candesartan significantly reduces LID in the 6-OHDA rat model. Chronic dopaminergic denervation induces an increase in striatal levels of VEGF and IL-1β. Dyskinetic animals showed significantly higher levels of VEGF and IL-1β in the lateral striatum and the substantia nigra, as revealed by western blot and real time-PCR analyses. Interestingly, animals treated with both candesartan and l-dopa displayed significantly lower levels of VEGF, IL-1β and dyskinesia than those treated with l-dopa alone. The stimulatory effect of angiotensin II (AII) on VEGF expression was confirmed by the addition of AII to primary mesencephalic cultures and intraventricular administration of AII in rats. The results of the present study reveal for the first time that blockage of AT-1 receptors reduces LID. A candesartan-induced decrease in VEGF and IL-1β may be responsible for the beneficial effects, suggesting the brain RAS as a new target for LID treatment in PD patients.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Muñoz
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garrido-Gil
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Dominguez-Meijide
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain. Electronic address: joseluis.labandeira@usc.es.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D013777:Tetrazoles / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D018663:Adrenergic Agents; D047228:Angiotensin II Type 1 Receptor Blockers; D000978:Antiparkinson Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D053583:Interleukin-1beta; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D007980:Levodopa; D016627:Oxidopamine; C081643:candesartan
keywords: Angiogenesis; Candesartan; Dopamine; Dyskinesia; Levodopa; Neuroinflammation; Parkinson; Renin–angiotensin system; VEGF