Contribution of the neuroinflamation to L-DOPA induced dyskinesia

• 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
• 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 18/20407-1 - New antipsychotic agents? Investigation of sinergic interaction between clozapine, doxicicline and/or canabidiol, BP.IC; 18/14569-9 - Effect of induced nitric oxide synthase (iNOS) deletion in the extrapyramidal symptoms in mice, BP.IC; 18/00461-1 - Dynamic Brain Imaging during Parkinson's disease and L-DOPA-induced dyskinesia: Investigation of commitment level of the blood-brain barrier and activation of glial cells (microglia and astrocytes), BP.PD; 17/14419-4 - Effect of interferon-³ on parkinsonism and on l-DOPA-induced dyskinesia, BP.MS; 17/05361-2 - Role of Toll-like receptor 4 (TLR4) in neuroinflammation and L-DOPA induced dyskinesia in mice, BP.IC; 16/06602-0 - Inflammatory process to L-DOPA-induced dyskinesia contribution in Parkinson's Disease, BP.PD - 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)

Scientific publications

(14)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FERREIRA JUNIOR, NILSON CARLOS; DOS-SANTOS-PEREIRA, MAURICIO; GUIMARAES, FRANCISCO SILVEIRA; DEL BEL, ELAINE. Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson's Disease and l-DOPA-Induced Dyskinesia. NEUROTOXICITY RESEARCH, OCT 2019. (12/17626-7, 14/25029-4, 17/14207-7)

DOS-SANTOS-PEREIRA, MAURICIO; GUIMARAES, FRANSCISCO S.; DEL-BEL, ELAINE; RAISMAN-VOZARI, RITA; MICHEL, PATRICK P.. Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-kappa B-dependent signaling and glucose consumption. Glia, v. 68, n. 3, p. 561-573, MAR 2020. (18/03482-0, 14/25029-4, 17/14207-7)

FERRARI, D. P.; BORTOLANZA, M.; DEL BEL, E. A.. Interferon-gamma Involvement in the Neuroinflammation Associated with Parkinson's Disease and L-DOPA-Induced Dyskinesia. NEUROTOXICITY RESEARCH, v. 39, n. 3, p. 15-pg., 2021-03-09. (17/14419-4, 14/25029-4)

GRANO, F.; DEL-BEL, E.. Blood-brain barrier breakdown in an adult mouse model of Parkinson's disease. MOVEMENT DISORDERS, v. 34, p. 1-pg., 2019-10-01. (18/00461-1, 14/25029-4)

FERREIRA JUNIOR, NILSON CARLOS; DOS-SANTOS-PEREIRA, MAURICIO; GUIMARAES, FRANCISCO SILVEIRA; DEL BEL, ELAINE. Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson's Disease and l-DOPA-Induced Dyskinesia. NEUROTOXICITY RESEARCH, v. 37, n. 1, p. 18-pg., 2019-10-22. (17/14207-7, 12/17626-7, 14/25029-4)

PEDRAZZI, JOAO F. C.; SALES, AMANDA J.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.; CRIPPA, JOSE A. S.; DEL BEL, ELAINE. annabidiol prevents disruptions in sensorimotor gating induced by psychotomimetic drugs that last for 24-h with probable involvement of epigenetic changes in the ventral striatu. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 111, DEC 20 2021. (15/06515-8, 14/25029-4, 17/24304-0)

NASCIMENTO, GLAUCE CRIVELARO; DE PAULA, BRUNA BALBINO; FERRARI, DANIELE P.; IYOMASA, DANIELA MIZUSAKI; PEREIRA, YAMBA C. L.; PEDRAZZI, JOAO F.; BORTOLANZA, MARIZA; ISSY, ANA CAROLINA; MARDEGAN ISSA, JOAO PAULO; LEITE-PANISSI, CHRISTIE R. A.; et al. Upregulation of FosB/Delta FosB in limbic circuits after tooth exodontia-induced occlusal instability in an experimental model of unpredictable chronic stress. Brain Research Bulletin, v. 176, p. 142-150, NOV 2021. (17/24304-0, 18/05146-7, 14/25029-4, 15/03053-3)

FERRARI, D. P.; BORTOLANZA, M.; DEL BEL, E. A.. Interferon-gamma Involvement in the Neuroinflammation Associated with Parkinson's Disease and L-DOPA-Induced Dyskinesia. NEUROTOXICITY RESEARCH, MAR 2021. (14/25029-4, 17/14419-4)

BORTOLANZA, MARIZA; DO NASCIMENTO, GLAUCE C.; RAISMAN-VOZARI, RITA; DEL-BEL, ELAINE. Doxycycline and its derivative, COL-3, decrease dyskinesia induced by l-DOPA in hemiparkinsonian rats. British Journal of Pharmacology, v. 178, n. 13, APR 2021. (14/25029-4, 17/24304-0)

DOMINGUEZ-MEIJIDE, ANTONIO; PARRALES, VALERIA; VASILI, EFTYCHIA; GONZALEZ-LIZARRAGA, FLORENCIA; KONIG, ANNEKATRIN; LAZARO, DIANA F.; LANNUZEL, ANNIE; HAIK, STEPHANE; DEL BEL, ELAINE; CHEHIN, ROSANA; et al. Doxycycline inhibits alpha -synuclein-associated pathologies in vitro and in vivo. Neurobiology of Disease, v. 151, APR 2021. (14/25029-4)

CARTA, ANNA R.; MULAS, GIOVANNA; BORTOLANZA, MARIZA; DUARTE, TERENCE; PILLAI, ELISABETTA; FISONE, GILBERTO; VOZARI, RITA RAISMAN; DEL-BEL, ELAINE. L-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role?. European Journal of Neuroscience, v. 45, n. 1, p. 73-91, JAN 2017. (12/17626-7, 14/25029-4)

CARTA, ANNA R.; MULAS, GIOVANNA; BORTOLANZA, MARIZA; DUARTE, TERENCE; PILLAI, ELISABETTA; FISONE, GILBERTO; VOZARI, RITA RAISMAN; DEL-BEL, ELAINE. l-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role?. European Journal of Neuroscience, v. 45, n. 1, SI, p. 73-91, JAN 2017. (12/17626-7, 14/25029-4)

GONZALEZ-LIZARRAGA, FLORENCIA L.; PLOPER, DIEGO; AVILA, CESAR L.; SOCIAS, SERGIO B.; DOS-SANTOS-PEREIRA, MAURICIO; MACHIN, BELEN; DEL-BEL, ELAINE; MICHEL, PATRICK PIERRE; PIETRASANTA, I, LIA; RAISMAN-VOZARI, RITA; et al. CMT-3 targets different alpha-synuclein aggregates mitigating their toxic and inflammogenic effects. SCIENTIFIC REPORTS, v. 10, n. 1, NOV 20 2020. (17/24304-0, 18/03482-0, 14/25029-4, 17/14207-7)

DOS SANTOS PEREIRA, MAURICIO; ABREU, GABRIEL HENRIQUE DIAS; ROCCA, JEREMY; HAMADAT, SABAH; RAISMAN-VOZARI, RITA; MICHEL, PATRICK PIERRE; DEL BEL, ELAINE. Contributive Role of TNF-alpha to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson's Disease. FRONTIERS IN PHARMACOLOGY, v. 11, JAN 11 2021. (14/25029-4, 18/03482-0, 17/24304-0, 17/14207-7)