The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells

• Grant number: 17/14207-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2017
• End date: March 22, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Elaine Aparecida Del Bel Belluz Guimarães
• Grantee: Maurício dos Santos Pereira
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders, AP.TEM
• Associated scholarship(s): 18/03482-0 - The action of cannabinoid drugs in glial-derived neuroinflammation process: a link to L-dopa-induced dyskinesia, BE.EP.PD

Abstract

The loss of dopaminergic (DA) neurons in Parkinson's disease (PD) is accompanied by persistent neuroinflammatory reactions mediated by astrocytes and microglial cells. This process, which is not yet fully characterized, probably perpetuates and amplifies the progression of this disorder. The DA precursor, L-DOPA, remains the most efficient treatment for PD 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 LID, since a pro-inflammatory environment in the striatum can be induced by excessive levels of glutamate and 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 that drugs related to the endocannabinoid system may attenuate the dyskinesia that develops after chronic dopaminergic replacement therapy. Recent data from our group indicate that treatment with cannabidiol, the main non-psychomimetic compound of Cannabis sativa, together with the TRPV-1 receptor antagonist capsazepine is able to reduce LID by reducing inflammatory factors such as the cyclooxygenase-2 enzyme and the protooncogene NF-™B. However, the involvement of glial cells in the LID, its action on glutamatergic imbalance existent in this pathology and, mainly, the effect of cannabinoid drugs on them is still incipient. Based on this, the proposed project has three main objectives: (i) to investigate whether mimetic compounds F101 (synthetic analogue of cannabidiol) and HU-910 (synthetic analogue of CB2 agonists) are able to reduce LID. As LID may be a consequence of an abnormal glutamate increase in the striatum, which may lead to neuroinflammation, we will also use the microglial glutamate transporter inhibitor sulfasalazine ; (Ii) to analyze, in vitro, whether treatment with L-DOPA/DA or glutamate generates an inflammatory process in astrocytes and microglia, comparing them to a classic inflammatory agent, LPS; (Iii) investigate whether F101 or HU910 are capable of altering the production of cytokines and glutamate in astrocytes and microglia using sulfasalazine as control. To do this, we will use a previously developed L-DOPA induced dyskinesia model, well characterized by the Brazilian team and a recently developed in vitro glial cell system, through collaboration with a French team to use as a model of neuroinflammatory reactions relevant to dyskinesia. (AU)

Scientific publications

(7)

(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)

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)

FERREIRA JUNIOR, NILSON CARLOS; PEREIRA, MAURICIO DOS SANTOS; FRANCIS, NOUR; RAMIREZ, PAOLA; MARTORELL, PAULA; GONZALEZ-LIZARRAGA, FLORENCIA; FIGADERE, BRUNO; CHEHIN, ROSANA; DEL BEL, ELAINE; RAISMAN-VOZARI, RITA; et al. The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress. CELLS, v. 10, n. 8, AUG 2021. (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)

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)

KUBRUSLY, REGINA CELIA CUSSA; DA ROSA VALLI, THAIS; FERREIRA, MARIANA NUNES MARINHO RITTER; DE MOURA, PAMELLA; BORGES-MARTINS, VLADIMIR PEDRO PERALVA; MARTINS, ROBERTTA SILVA; FERREIRA, DANIELLE DIAS PINTO; SATHLER, MATHEUS FIGUEIREDO; DE MELO REIS, RICARDO AUGUSTO; FERREIRA, GUSTAVO COSTA; et al. Caffeine Improves GABA Transport in the Striatum of Spontaneously Hypertensive Rats (SHR). NEUROTOXICITY RESEARCH, OCT 2021. (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)

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)