New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders

• Grant number: 17/24304-0
• Support type: Research Projects - Thematic Grants
• Duration: February 01, 2019 - January 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal researcher: Francisco Silveira Guimaraes
• Grantee: Francisco Silveira Guimaraes
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Elaine Aparecida Del Bel Belluz Guimarães ; Leonardo Resstel Barbosa Moraes ; Sâmia Regiane Lourenço Joca
• Assoc. researchers: Alline Cristina de Campos ; Ana Carolina de Castro Issy Pereira ; Ana Luisa Bernardes Terzian ; Antonio Cardozo dos Santos ; Ariandra Guerini Sartim ; Claudia Maria de Castro Batista ; Cristina Aparecida Jark Stern ; Daniele Cristina de Aguiar ; Elaine Aparecida Del Bel Belluz Guimarães ; Fabricio de Araujo Moreira ; Fernanda Grecco Grano ; Fernando Morgan de Aguiar Correa ; Frederico Rogério Ferreira ; Glauce Crivelaro Do Nascimento ; Leandro José Bertoglio ; Mariza Bortolanza ; Maurício dos Santos Pereira ; Nilson Carlos Ferreira Junior ; Pedro Henrique Gobira Nunes ; Rúbia Maria Monteiro Weffort de Oliveira ; Sabrina Francesca de Souza Lisboa
• Associated scholarship(s): 22/00198-4 - Involvement of nitric oxide with the behavioural and molecular changes induced by exposure to an intense stressor: possible effect of cannabidiol, BP.PD; 22/00197-8 - Involvement of the medial prefrontal cortex (mPFC) in the rapid and sustained effect of drugs in a model of depression resistant to conventional antidepressants: possible involvement of endocannabinoid modulation on the cortical glutamatergic system, BP.PD; 21/12917-2 - New perspectives on the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders, BP.TT; + associated scholarships 20/02297-4 - Conditioned and unconditioned stimulus send at fixed or randomized intervals: possible behavioral differences for the expression and extinction of conditioned fear memory, BP.IC; 20/04145-7 - Investigation of the possible involvement of adenosinergic receptors in the behavioral effects induced by cannabidiol in mice using different animal models, BP.IC; 19/26351-0 - Evaluation of paclitaxel-induced cognitive deficits in a 4T-1 murine mammary carcinoma model and possible protective effect of concomitant cannabidiol treatment, BP.IC; 19/24591-4 - Mechanisms of cannabidiol antipsychotics effects in schizophrenia model based in neurodevelopment variation, BP.DR; 19/18846-0 - Role of the endocannabinoid system in orofacial muscular pain related to Parkinson's Disease, BP.IC; 19/26810-5 - Extracellular vesicles as signals of the hippocampal neurogenic niche: participation in the behavioral effects of cannabinoid and antidepressant drugs, BP.PD; 18/15896-3 - Participation of DNA methylation in rapid and sustained antidepressant-like effects induced by Cannabidiol and Ketamine, BP.PD; 18/20433-2 - Neuroprotective and behavioral effects of the PPAR³ agonist pioglitazone in a neurodevelopmental model of schizophrenia, BP.PD; 17/14207-7 - The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells, BP.PD - associated scholarships

Abstract

The need to develop new therapeutic targets for the treatment of neuropsychiatric disorders is a consensus in the scientific literature. Endocannabinoids (eCBs) and nitric oxide (NO) have been proposed as two of these possible targets. Studies from our group have disclosed the therapeutic potential of drugs that interfere with these two atypical neurotransmitters in anxiety, depressive, psychotic disorders, Parkinson's disease, aggressive behavior and neurodegeneration/neurotoxicity. Cannabidiol (CBD), a non-psychotomimetic phytocannabinoid, which, among other effects, can increase the levels of the eCB anandamide, is already undergoing clinical trials to test its efficacy in some of these disorders. However, several important questions still remain related to the therapeutic potential of these drugs in other specific disorders as well as to the mechanisms involved. In the last few years our studies have indicated new possibilities, including facilitation of adult hippocampal neurogenesis and autophagy and the possible involvement of neuroinflammatory/neuroimmune mechanisms. The present project aimed at continuing this research line, trying to investigate 1. Which is the involvement and mechanisms of the anti-inflammatory effects of CBD and drugs that modify the NO and eCB system in their potential therapeutic effects?; 2. Which other neuropsychiatric disorders could benefice from these drugs?; 3. In case of co-morbities such as metabolic syndrome and anxiety disorders, in which an inflammatory component is present, would these new therapies be effective?; 4. Which other intra-cellular pathways would be involved?; 5. Which is the specific eCB involvement in the modulation of rewarding and aversive responses?; 6. Which specific epigenetic mechanisms are involved with these effects? (AU)

Scientific publications

(27)

(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)

HARTMANN, ALICE; LISBOA, SABRINA FRANCESCA; SONEGO, ANDREZA BUZOLIN; COUTINHO, DEBORA; GOMES, FELIPE VILLELA; GUIMARAES, FRANCISCO SILVEIRA. Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 94, AUG 30 2019. (16/14282-6, 10/17343-0, 17/24304-0, 11/22523-0, 17/19731-6)

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)

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)

RIBEIRO, MELISSA A.; AGUIAR, RAFAEL P.; SCARANTE, FRANCIELE F.; FUSSE, EDUARDO J.; DE OLIVEIRA, RUBIA M. W.; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE C.. pontaneous Activity of CB2 Receptors Attenuates Stress-Induced Behavioral and Neuroplastic Deficits in Male Mic. FRONTIERS IN PHARMACOLOGY, v. 12, JAN 21 2022. (17/24304-0, 15/05551-0)

ULIANA, DANIELA L.; ANTERO, LEANDRO S.; BORGES-ASSIS, ANNA B.; ROSA, JESSICA; VILA-VERDE, CARLA; LISBOA, SABRINA F.; RESSTEL, LEONARDO B. M.. Differential modulation of the contextual conditioned emotional response by CB1 and TRPV1 receptors in the ventromedial prefrontal cortex: Possible involvement of NMDA/nitric oxide-related mechanisms. JOURNAL OF PSYCHOPHARMACOLOGY, v. 34, n. 9, JUL 2020. (17/24304-0, 17/14473-9)

HEIMANN, ANDREA S.; DALE, CAMILA S.; GUIMARAES, FRANCISCO S.; REIS, RICARDO A. M.; NAVON, AMI; SHMUELOV, MICHAL A.; RIOLI, VANESSA; GOMES, IVONE; DEVI, LAKSHMI L.; FERRO, EMER S.. Hemopressin as a breakthrough for the cannabinoid field. Neuropharmacology, v. 183, FEB 1 2021. (16/04000-3, 19/06982-6, 17/24304-0)

ZADOR, FERENC; JOCA, SAMIA; NAGY-GROCZ, GABOR; DVORACSKO, SZABOLCS; SZUCS, EDINA; TOMBOLY, CSABA; BENYHE, SANDOR; VECSEI, LASZLO. Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 11, JUN 2021. (17/24304-0)

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)

BATISTA, LUARA AUGUSTA; DE ARAUJO MOREIRA, FABRICIO; DE AGUIAR, DANIELE CRISTINA. Interactions between the nitrergic and the endocannabinoid system in rats exposed to the elevated T-maze. ACTA NEUROPSYCHIATRICA, v. 33, n. 4, p. 206-210, AUG 2021. (17/24304-0)

SILVA, NICOLE RODRIGUES; GOMES, FRANCISCO ISAAC FERNANDES; LOPES, ALEXANDRE HASHIMOTO PEREIRA; CORTEZ, ISADORA LOPES; DOS SANTOS, JESSICA CRISTINA; SILVA, CONCEICAO ELIDIANNE ANIBAL; MECHOULAM, RAPHAEL; GOMES, FELIPE VILLELA; CUNHA, THIAGO MATTAR; GUIMARAES, FRANCISCO SILVEIRA. The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPAR gamma Receptors. NEUROTHERAPEUTICS, DEC 2021. (17/24304-0)

MEYER, ERIKA; BONATO, JESSICA MENDES; MORI, MARCO AURELIO; MATTOS, BIANCA ANDRETTO; GUIMARAES, FRANCISCO SILVEIRA; MILANI, HUMBERTO; DE CAMPOS, ALLINE CRISTINA; WEFFORT DE OLIVEIRA, RUBIA MARIA. Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity. Molecular Neurobiology, v. 58, n. 10, JUL 2021. (17/24304-0)

MACIEL, IZAQUE DE SOUSA; SALES, AMANDA J.; CASAROTTO, PLINIO C.; CASTREN, EERO; BIOJONE, CAROLINE; JOCA, SAMIA R. L.. Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats. European Journal of Neuroscience, DEC 2020. (15/25067-6, 15/06271-1, 17/24304-0)

SARTIM, A. G.; MARQUES, J.; SILVEIRA, K. M.; GOBIRA, P. H.; GUIMARAES, F. S.; WEGENER, G.; JOCA, S. R.. Co-administration of cannabidiol and ketamine induces antidepressant-like effects devoid of hyperlocomotor side-effects. Neuropharmacology, v. 195, SEP 1 2021. (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)

ROPKE, JIVAGO; FERREIRA-VIEIRA, TALITA H.; IGLESIAS, LIA P.; ASTH, LAILA; RIBEIRO, FABIOLA M.; MOREIRA, FABRICIO A.. Protective role of endocannabinoid signaling in an animal model of haloperidol-induced tardive dyskinesia. Pharmacology Biochemistry and Behavior, v. 206, JUL 2021. (17/24304-0)

SILVEIRA, KENNIA M.; WEGENER, GREGERS; JOCA, SAMIA R. L.. Targeting 2-arachidonoylglycerol signalling in the neurobiology and treatment of depression. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. 129, n. 1, p. 3-14, JUL 2021. (17/24304-0)

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. (14/25029-4, 15/06515-8, 17/24304-0)

CORTEZ, ISADORA L.; RODRIGUES DA SILVA, NAIELLY; GUIMARAES, FRANCISCO S.; GOMES, FELIPE V.. Are CB2 Receptors a New Target for Schizophrenia Treatment?. FRONTIERS IN PSYCHIATRY, v. 11, OCT 30 2020. (17/24304-0, 18/17597-3)

IGLESIAS, LIA P.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A.. TRPV1 blockers as potential new treatments for psychiatric disorders. Behavioural Pharmacology, v. 33, n. 1, p. 2-14, FEB 2022. (17/24304-0)

DA SILVA, NAIELLY RODRIGUES; GOMES, FELIPE VILLELA; SONEGO, ANDREZA BUZOLIN; DA SILVA, NICOLE RODRIGUES; GUIMARAES, FRANCISCO SILVEIRA. Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors. PHARMACOLOGICAL RESEARCH, v. 156, JUN 2020. (17/24304-0, 18/17597-3)

LOPES, JADNA B.; BASTOS, JULIANA R.; COSTA, RAYSSA B.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A.. The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice. Psychopharmacology, OCT 2019. (17/24304-0)

RAYMUNDI, ANA MARIA; DA SILVA, THIAGO R.; ZAMPRONIO, ALEKSANDER R.; GUIMARAES, FRANCISCO S.; BERTOGLIO, LEANDRO J.; STERN, CRISTINA A. J.. A time-dependent contribution of hippocampal CB1, CB2 and PPAR gamma receptors to cannabidiol-induced disruption of fear memory consolidation. British Journal of Pharmacology, v. 177, n. 4, SI, JAN 2020. (17/24304-0)

GOBIRA, P. H.; RONCALHO, A. L.; SILVA, N. R.; SILOTE, G. P.; SALES, A. J.; JOCA, S. R.. Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice. Psychopharmacology, v. 238, n. 11, JUL 2021. (17/19284-0, 17/24304-0)

SANTOS-LOBATO, BRUNO L.; BORTOLANZA, MARIZA; PINHEIRO, LUCAS CESAR; BATALHAO, MARCELO E.; PIMENTEL, ANGELA V.; CAPELLARI-CARNIO, EVELIN; DEL-BEL, ELAINE A.; TUMAS, VITOR. Levodopa-induced dyskinesias in Parkinson's disease increase cerebrospinal fluid nitric oxide metabolites' levels. JOURNAL OF NEURAL TRANSMISSION, v. 129, n. 1, DEC 2021. (17/24304-0, 12/17626-7)

ASTH, LAILA; IGLESIAS, LIA P.; BRIANIS, RAYSSA C.; MARCAL, ANNA P.; SOARES, NICIA P.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A.. Effects of the monoamine stabilizer, (-)-OSU6162, on cocaine-induced locomotion and conditioned place preference in mice. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. 394, n. 6, JAN 2021. (17/24304-0)

SCARANTE, FRANCIELE F.; RIBEIRO, MELISSA A.; ALMEIDA-SANTOS, ANA F.; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE C.. Glial Cells and Their Contribution to the Mechanisms of Action of Cannabidiol in Neuropsychiatric Disorders. FRONTIERS IN PHARMACOLOGY, v. 11, FEB 4 2021. (19/25984-0, 19/09178-3, 17/24304-0)

MORI, MARCO AURELIO; MEYER, ERIKA; DA SILVA, FRANCIELLY F.; MILANI, HUMBERTO; GUIMARAES, FRANCISCO SILVEIRA; OLIVEIRA, RUBIA MARIA WEFFORT. Differential contribution of CB1, CB2, 5-HT1A, and PPAR-gamma receptors to cannabidiol effects on ischemia-induced emotional and cognitive impairments. European Journal of Neuroscience, v. 53, n. 6, FEB 2021. (17/24304-0)