Investigation of P2X7 receptors and the NLRP3 inflammasome in the extinction deficits observed in a genetic model of PTSD

• Grant number: 23/01328-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2023
• End date: June 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Sabrina Francesca de Souza Lisboa
• Grantee: Karen Eduarda Barbosa
• 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

We previously demonstrated that iNOS knockout animals show deficits in the extinction of contextual conditioned fear (Lisboa et al., 2015 doi: 10.1093/ijnp/pyv005). We also saw that this behavior could result from a compensatory increase in NO production in the medial prefrontal cortex (mPFC) of these animals, but not in the hippocampus, via nNOS, since the inhibition of this isoform normalized the behavior of these animals. In addition, these animals show an increase in nNOS expression in the mPFC, which could partly explain the extinction deficits, since these alterations are related to extinction deficits. It is known that aberrant NO production can contribute to increased production of reactive oxygen species (ROS) by mitochondria, which may result in activation of the NLRP3 inflammasome (Baie et al., 2020, doi.org/10.1038/s41419- 020-02985-x). Furthermore, P2X7 blockade in a cerebral hemorrhage model prevents NLRP3 activation and oxidative stress (Fenge et al., 2015 10.1186/s12974-015-0409-2) and NOS inhibitors induce antidepressant-like effect involving reduction of the NLRP3 pathway (Ozkartal et al., 10.1016/j.brainres.2019.146438). Thus, the aim of this project is to assess whether the extinction deficits observed in iNOS KO animals, a genetic model, are accompanied by activation of P2X7 and NLRP3 inflammasome in the brain of the animals, as well as changes in oxidant/antioxidant mechanisms. Furthermore, whether they are attenuated by treatment with A-438079, a P2X7 antagonist, or with MCC950, an NLRP3 inhibitor.