Bipolar disorder models: Oxidative stress response in neuronal cortical primary culture from Poly (I:C) treated with Ouabain

• Grant number: 24/10559-0
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: September 02, 2024
• End date: January 01, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Cristoforo Scavone
• Grantee: Vitória Cristina Araujo
• Supervisor: Juan-Carlos Leza
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universidad Complutense de Madrid (UCM), Spain
• Associated to the scholarship: 23/01789-9 - OUABAIN EFFECTS ON CHANGES IN MITOCHONDRIAL FUNCTION AND THE NEUROGENESIS PROCESS IN CORTICAL NEURONAL CELLS EXPOSED TO ROTENONE, BP.IC

Abstract

Characterized by a combination of manic and depressive episodes that affects 3% of the global population, Bipolar Disorder (BD) is a severe psychiatric illness that highly affects patients' lives. Its pathology is not completely understood but is associated with disturbances in Na+K+ATPase (NKA) function, mitochondrial function, inflammatory process, and oxidative response. In that context, the NKA role in BD development can be demonstrated by the fact that Ouabain, an NKA inhibitor, is highly used as an inductor of the BD model in animals. This drug injection in rats can mimic the disorder symptoms - manic-like behaviors, as increased locomotor activity, and depressive-like behaviors, like decreased food consumption-, pathophysiologic alterations, and its response to the classic treatment. On the other hand, in cortical neuronal primary cells, our previous studies have shown that Ouabain treatment affects mitochondrial parameters, such as basal and maximal respiration, spare capacity, and ATP production. In other aspects, regarding the inflammatory influence in BD, maternal immune activation (MIA) is highly related to neuropsychiatric disorders development later in life, once it causes alterations in neurotransmitters and important cellular signaling pathways. Thus, Poly (I:C) exposure during pregnancy induces a cytokine acute response capable of inducing psychiatric illness development in offspring. Therefore, this project aims to compare the oxidative response anomalies in primary cortical neurons from an MIA animal model (PolyI:C), with primary cortical neurons treated with Ouabain. In addition to that, we want to see if the Ouabain treatment can worsen the Poly (I:C) irregularities. To achieve that, we will use embryos 19 days old from Poly (I:C) treated Wistar rats and treated control Wistar rats to obtain a primary cortical neuronal culture. Then, both cells will be treated with Ouabain (10uM) and the vehicle (DMSO). After that, we will evaluate antioxidant cascade proteins. In that way, we'll be able to compare the importance of the different aspects - NKA dysfunctions, mitochondrial alterations, inflammatory response, and oxidative alteration - of BD pathogenesis.