| Grant number: | 14/25029-4 |
| Support Opportunities: | Research Projects - Thematic Grants |
| Start date: | April 01, 2016 |
| End date: | December 31, 2019 |
| Field of knowledge: | Biological Sciences - Pharmacology - Neuropsychopharmacology |
| Principal Investigator: | Elaine Aparecida Del Bel Belluz Guimarães |
| Grantee: | Elaine Aparecida Del Bel Belluz Guimarães |
| Host Institution: | Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil |
| City of the host institution: | Ribeirão Preto |
| Associated researchers: | Vitor Tumas ; Wilson Marques Junior |
| Associated scholarship(s): | 19/17320-4 - Qualification immunohistochemical and histological techniques analysis in optical microscopy,
BP.TT 19/02300-8 - Doxycycline effects in the haloperidol-induced tardive dyskinesia, BP.IC 18/25524-6 - Qualification in immunohistochemical and histological techniques and analysis in optical microscopy, BP.TT + associated scholarships - associated scholarships |
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). We shall test the hypothesis thought out serum and liquor of Parkinson's disease patients. (AU)
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