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Investigation of the participation of the ADAM10-NEGR1-FGFR2 pathway in vitro and in vivo effects of Cannabidiol in stress conditions

Grant number: 22/01192-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2023
Effective date (End): December 31, 2024
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Sabrina Francesca de Souza Lisboa
Grantee:Izabela Pereira Vatanabe
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:17/19731-6 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD), AP.JP

Abstract

The ADAM10-NEGR1-FGFR2 pathway plays a key role in the development of the neural structure. Evidence shows that the biology of this pathway influences several neuropsychiatric conditions and disorders, such as anxiety and depression, Alzheimer's Disease (AD), Autism Spectrum Disorder - ASD and schizophrenia, even obesity. Recent results have indicated that the biology of this pathway is related to the molecular events underlying therapeutic interventions with some antidepressants. However, several limitations involve the use of these medications, including delay in therapeutic response, diversity of side effects, a large percentage of people unresponsive to treatment, among others. In this way, Cannabidiol (CBD) has been shown to be an important effective alternative in the treatment of these and the other conditions, with evidence of rapid action, sustained effects, and a better profile of side effects. Although numerous therapeutic targets have already been described, the interaction of CBD with the ADAM10-NEGR1-FGRF2 pathway is not yet known. Thus, this work aims to investigate, in a stress model, in vitro and in vivo, whether the effects of CBD involve the modulation of the ADAM10-NEGR1-FGFR2 pathway. For this, differentiated SH-SY5Y cells and adult male and females C57BL/6 mice will be exposed to chronic stress induced by corticosterone and later, still facing the stressor stimulus, treatments with the vehicle, CBD, Escitalopram, and Nortriptyline will be administered. In another experiment, ADAM10 will be pharmacologically inhibited, in vitro, to assess whether the effects of CBD depend on this pathway. Cell viability will be assessed for all treatments. To evaluate the effects of CBD and the other drugs against the stressor stimulus, the levels of active ADAM10 (60 kDa), NEGR1 and FGFR2 will be quantified in cells and in biological materials from animals (platelets, hippocampus and cortex). In addition, changes in dendritic ramifications will be evaluated. Additionally, physical, dietary, behavioral, and cognitive measures will be analyzed in vivo, in order to verify the effectiveness of the treatment performed with CBD and the efficiency of the chosen stress model. With this same intention, the production of Reactive Oxygen Species (ROS) will be properly measured in vitro. It is expected that the results of this study may contribute to the elucidation of CBD's mechanism of action, as well as open new therapeutic possibilities for the treatment of a range of disorders that present alterations in the ADAM10-NEGR1-FGRF2 pathway.

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