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Inflammatory process to L-DOPA-induced dyskinesia contribution in Parkinson's Disease

Grant number: 16/06602-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2016
Effective date (End): December 31, 2019
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Elaine Aparecida Del Bel Belluz Guimarães
Grantee:Mariza Bortolanza
Home Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/25029-4 - Contribution of the neuroinflamation to L-DOPA induced dyskinesia, AP.TEM

Abstract

L-3, 4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson´s disease but can induce debilitating abnormal involuntary movements (dyskinesia). The precise mechanisms underlying the process remain to be clarified. However, some recent studies have suggested that L-DOPA-induced dyskinesia may be related to a "pro-inflammatory" environment in the striatum. Our group discovered that L-DOPA-induced dyskinesia in hemiparkinsonian rodents could be attenuated with NOS inhibitors, such as (7-nitroindazole [7-NI] or NG-nitro-L-arginine [L-NOARG]), without altering L-DOPA-induced motor improvements. Nitric oxide (NO) has been proposed to have a role in inflammation and in the inflammatory processes in Parkinson's disease. In this study, we will use hemiparkinsonian mice to determine whether L-DOPA-induced dyskinesia is associated with pro-inflammatory glial reactions in the striatum and substantia nigra and whether these responses can be modulated by cotreatment with the preferential nNOS inhibitor 7-NI and other compounds with neuroinflammatory/antioxidant activity: doxycycline, canabidiol and celecoxibe. Male C57BL mice, wild type and knockout for the cytokine fraktalcne (CX3CR1GFP/GFP), Toll-9 and TOLL-4 receptor, will receive unilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. After three weeks animals started to receive daily treatment with L-DOPA (25 mg/kg) plus benserazide (7.5 mg/kg), for 21 days, combined with an inhibitor of neuronal NOS (7-nitroindazole, 7-NI, 30 mg/kg/day) or vehicle (saline-PEG 50%) or the drugs described above. Our aims are (i) to determine the treatment affects on the dyskinesia development (ii) to determine citokines and lipid mediators in the animals dopamine depleted striatum (interleukine-1 and BDNF); (iii) to analyze in the brain of L-DOPA-treated dyskinetic animals the expression of glial fibrillary acidic protein (GFAP) in reactive astrocytes, an increased number of CD11b-positive microglial cells with activated morphology, and the cells positive for inducible nitric oxide-synthase immunoreactivity (iNOS). (AU)

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