Effects of the beta-carboline alkaloids harmine and harmaline on the Nrf2-mediated antioxidant defense pathway in a cellular and animal model of LPS-induced neuroinflammation

• Grant number: 23/02031-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fulvio Rieli Mendes
• Grantee: Gabriela Morales Lima
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated scholarship(s): 24/18859-2 - Investigating the role of natural products on oxidative stress and mitochondrial function: an in vitro and in vivo approach, BE.EP.MS

Abstract

Alzheimer's disease is a neurodegenerative disorder responsible for approximately 50-70% of diagnosed dementia cases and directly affects patients' quality of life. Although its pathogenesis is not yet fully understood, a number of metabolic alterations have already been identified as important components in disease progression, including mechanisms of oxidative stress and neuroinflammation. In this context, screening of compounds capable of modulating intracellular pathways of inflammatory response and antioxidant defense is considered promising therapeutic or prophylactic agents. Several studies have pointed to the potential of natural products as inducers of the Nrf2 transcription factor antioxidant response pathway. Therefore, the aim of this project is to investigate the potential protective effects of the ²-carboline alkaloids harmine and harmaline - which are present in plants such as P. harmala and B. caapi - in a model of LPS-induced neuroinflammation and oxidative stress. To this end, cell cultures will be used to investigate whether ²-carbolines are able to attenuate the damage of PC12 cells treated with the conditioned medium of C6 cells exposed to LPS, and the transcription factors Nrf2 and NF-ºB will be used as indicators of oxidative stress and neuroinflammation, respectively. In addition, C57BL6 mice will be subjected to a paradigm of cognitive impairment induced by systemic administration of LPS, undergoing open-field, object discrimination, and passive avoidance tests. After behavioral assessment, postmortem activity of enzymes associated with the antioxidant response related to the Nrf2 pathway (SOD, CAT, and GSH-Px) and GSH levels will be evaluated, in addition to spontaneous lipid peroxidation, and AChE activity.