Investigation of the therapeutic profile of cannabidiol in an animal model of Autism Spectrum Disorder

• Grant number: 22/05199-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2023
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: José Alexandre de Souza Crippa
• Grantee: João Francisco Cordeiro Pedrazzi
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction and restricted or repetitive motor movements often associated with cognitive deficits. ASD is observed in early childhood, with a higher prevalence in males. Although it is among the most serious chronic childhood disorders in terms of prevalence, morbidity, and impact on society, there is still no effective treatment for ASD, possibly because its neurobiological basis is not clearly understood. Several studies have shown that exposure to valproic acid during pregnancy, a drug used to treat mood disorders and epilepsy, is associated with a higher incidence of ASD. Behavioral and molecular factors associated with this disorder include impairment in object recognition and social interaction tests, changes in the levels of monoamines and the enzyme glutamic acid decarboxylase, and increased neuroinflammation. There are still no specific drugs for the treatment of ASD. However, the administration of the hormone oxytocin in patients with this disorder has shown promising effects in improving their social skills. Additionally, clinical and preclinical trials strongly point to the involvement of the endocannabinoid system in the pathophysiology of this disorder. The observation that the levels of anandamide and CB1 receptors are altered in patients with ASD supports this hypothesis. Cannabidiol (CBD), the main constituent of Cannabis sativa, interacts with the endocannabinoid system and has great therapeutic potential in treating numerous psychiatric disorders, as observed in the clinic and animal preparations. However, there are still no studies investigating the therapeutic potential of CBD in the treatment of behavioral symptoms and molecular alterations of ASD in animal models. The general objective of this study is to investigate whether CBD can reverse behavioral impairments and molecular changes in male mice exposed to valproic acid in the embryonic period. In this sense, we will investigate: (I) the levels of monoamines: dopamine, serotonin, noradrenaline and their metabolites in brain structures (prefrontal cortex, hippocampus, dorsal and ventral striatum) after the prepulse inhibition test (PPI). (II) After the marble burying test, the expression of oxytocin in the paraventricular, supraoptic, and accumbens nuclei. (III and IV) Proteomic analysis in central nervous system structures (prefrontal cortex, hippocampus, ventral striatum, and cerebellum) after social interaction and object recognition. V) the expression of glial markers in limbic areas such as the prefrontal cortex, ventral striatum, and hippocampus. To carry out the assays, we will use as a positive control a selective antagonist for metabotropic glutamate receptors of subtype 5, the compound 2-methyl-6-phenylethyl-pyridine (MPEP), which has shown efficacy in animal models of autism. (AU)

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)

PEDRAZZI, JOAO F. C.; SILVA-AMARAL, DANYELLE; ISSY, ANA C.; GOMES, FELIPE V.; CRIPPA, JOSE A.; GUIMARAES, FRANCISCO S.; DEL BEL, ELAINE. Cannabidiol attenuates prepulse inhibition disruption by facilitating TRPV1 and 5-HT1A receptor-mediated neurotransmission. Pharmacology Biochemistry and Behavior, v. 245, p. 9-pg., 2024-09-21. (17/24304-0, 22/05199-9, 14/25029-4, 15/06515-8)

SIMEI, JOAO LUIS Q.; SOUZA, JOSE DIOGO R.; PEDRAZZI, JOAO FRANCISCO; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE CRISTINA; ZUARDI, ANTONIO; HALLAK, JAIME EDUARDO C.; CRIPPA, JOSE ALEXANDRE S.. Research and Clinical Practice Involving the Use of Cannabis Products, with Emphasis on Cannabidiol: A Narrative Review. PHARMACEUTICALS, v. 17, n. 12, p. 29-pg., 2024-12-01. (22/05199-9)

PEDRAZZI, J. F. C.; SALES, A. J.; PONCIANO, R. S. M.; FERREIRA, L. G.; FERREIRA, F. R.; CAMPOS, A. C.; HALLAK, J. E. C.; ZUARDI, A. W.; DEL BELAD, E. A.; GUIMARAES, F. S.; et al. Acute cannabidiol treatment reverses behavioral impairments induced by embryonic valproic acid exposure in male mice. Pharmacology Biochemistry and Behavior, v. 247, p. 9-pg., 2024-12-17. (22/05199-9, 17/24304-0)