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The action of cannabinoid drugs in glial-derived neuroinflammation process: a link to L-dopa-induced dyskinesia

Grant number: 18/03482-0
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): June 10, 2018
Effective date (End): June 01, 2019
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Elaine Aparecida Del Bel Belluz Guimarães
Grantee:Maurício dos Santos Pereira
Supervisor abroad: Rita Raisman Vozari
Home Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Institut National de la Santé et de la Recherche Médicale (Inserm), France  
Associated to the scholarship:17/14207-7 - The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells, BP.PD


Dopamine precursor L-DOPA remains the most efficient treatment for Parkinson's disease motor symptoms, at least in the early and middle stages of the disorder. However, chronic treatment with L-DOPA induces several non-motor and motor complications, including L-DOPA-induced dyskinesia (LID). Our hypothesis is that inflammatory mechanisms are also responsible for the LID, since a proinflammatory environment in the striatum can be induced by excessive levels of glutamate and dopamine (DA) released in the striatal extracellular fluid after administration of L-DOPA. Despite the large number of studies that propose new approaches for the treatment of LID, the effectiveness of new pharmacological treatments is still limited. Previous studies have shown drugs related to the endocannabinoid system may attenuate the dyskinesia that develops after chronic dopaminergic replacement therapy. Recent data from the group indicates that treatment with cannabidiol, the main non-psychomimetic compound of Cannabis sativa, together with the TRPV-1 receptor antagonist, is able to reduce LID by reducing inflammatory compounds, such as the cyclooxygenase-2 enzyme and the immediate response gene NF-™B. However, the involvement of glial cells in the LID and, mainly, the effect of cannabinoid drugs on them is still unknown. Based on that, our collaboration with the French team aims to analyze, in vitro, whether treatment with L-DOPA and DA or glutamate generates an inflammatory process in astrocytes and microglia, comparing them to a classic inflammatory agent, LPS. We also intend to investigate whether F101 or HU910 (drugs that act on the cannabinoid system) are capable of altering the production of cytokines and glutamate in astrocytes and microglia, using sulfasalazine (microglial glutamate release inhibitor) as control. To do this, we will use an in vitro model of newly developed glial cells through collaboration with the French team to use as a model of neuroinflammatory reactions relevant to LID. (AU)

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Scientific publications
(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)
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. Web of Science Citations: 0.
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; CHEHIN, ROSANA. CMT-3 targets different alpha-synuclein aggregates mitigating their toxic and inflammogenic effects. SCIENTIFIC REPORTS, v. 10, n. 1 NOV 20 2020. Web of Science Citations: 0.
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. Web of Science Citations: 0.

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