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Study of autophagy and neuroprotection mediated by cannabinoids compounds in vitro and in vivo models of Parkinson's Disease

Grant number: 20/08840-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2020
Effective date (End): July 31, 2022
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Soraya Soubhi Smaili
Grantee:Adolfo Garcia Erustes
Home Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). São Paulo , SP, Brazil
Associated research grant:19/02821-8 - Autophagy modulation by cannabinoids: neuroprotection in Parkinson's Disease, AP.TEM

Abstract

Parkinson's disease (PD) is the second neurodegenerative disorder most common. One of most know neuronal alteration described in PD is the protein aggregation, as consequence of failure in degradation of oxidates and malformed proteins. The cellular process that acts in the degradation of protein aggregates is the autophagy, which have been extensively investigated due its role in the therapeutics of many diseases, including the neurodegenerative diseases. In our research group, we developed and characterized the autophagy response in human neuroblastoma cell line (SH-SY5Y) overexpressing the protein ±-synuclein wild type and its mutants (A30P and A53T), that have been used as a cell model to PD. Many pharmacological agents that act in neuroprotection against protein aggregates has been identified, however pharmacologic manipulation that interferes in autophagic process in order to promote neuroprotection in neurodegenerative diseases are still scarce. A class of pharmacological agents that has been extensive explored and have potential neuroprotective role are the cannabinoids. In this way, the aim of our study is evaluate the main cellular pathways related to cannabinoid-induced autophagy in the neuroprotection against PD. The role of agonists, antagonists and pharmacological modulators derived from cannabinoid agents will be investigated, obtained from a standard library. The modulation of autophagy and the neuroprotection promoted by these compounds will be tested in experimental models of PD. The cannabinoid compounds will be selected from an initial screening for substances which can promotes the reduction of ±-synuclein aggregates in cellular models overexpressing WT or mutated forms of ±-synuclein, both in vitro and in vivo, using zebrafish. Thus, the molecular mechanisms of cannabinoids that regulates the autophagic process in neurodegenerative diseases will be studied, which are very important to basic research with translational perspectives. In this way, this study could act in the identification of new molecular targets that can be used to the development of new drugs.