Interrelationship of interleukin-6 and kynurenine pathway in cognitive and behavioral disorders induced by excessive exercise: in vivo and in vitro models

• Grant number: 22/06807-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2022
• Status: Discontinued
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: José Rodrigo Pauli
• Grantee: Alisson Luiz da Rocha
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated scholarship(s): 24/11074-0 - Dysregulation of KMO in the kynurenine pathway as a key mechanism in neurological disorders induced by exhaustive exercise, BE.EP.PD

Abstract

Athletes are usually exposed to strenuous training phases and, when the balance between training and recovery is not respected, they can develop the Overtraining Syndrome through excessive training. This phenomenon is characterized by a sustained physical performance decrement, and they generally present psychological disorders, such as anxiety and depression. Excessive training induces chronic low-grade inflammation and various maladaptations in the body. Interleukin-6 (IL-6) is a molecule that presents high levels in this situation and is closely linked to the development of depressive symptoms. It is important to note that inflammation, when dysregulated, induces disturbances in the Central Nervous System (CNS). Recently, the kynurenine (KYN) pathway has been highlighted as a promising target in the study of inflammatory, neurodegenerative and neurological disorders. This pathway is activated by IL-6 and produces neurotoxic metabolites that lead to maladaptations in the CNS. The hippocampus is an extremely sensitive region to exercise and inflammation. Changes in this brain region can develop neurodegenerative diseases and neurological disorders, such as depression. Briefly, excessive training can induce disorders in CNS through pathological activation of the IL-6/KYN pathway. Thus, the main aim of the present project is to analyze the relationship between IL-6 and the KYN pathway in the hippocampus of mice submitted to excessive training. Four experimental designs will be utilized: 1) Wild Type (WT) and IL-6 knockout (IL-6-/-) mice that will perform the excessive training protocol; 2) WT mice that will receive intracerebroventricular (ICV) injection of IL-6 at low (physiological) or high (pathological) doses; 3) WT mice that will be treated with an inhibitor of the KYN pathway enzyme (KMO) responsible for producing neurotoxic metabolites and will be submitted to the excessive training protocol; 4) mouse hippocampal neuronal cells (HT-22) that will be cultured in medium with low and high concentrations of IL-6 and selective inhibitors of KYN pathway enzymes. Mice will perform behavioral tests after the excessive training period. Neuronal cells and hippocampus will be collected and subjected to the following analyses: cell viability, Real-time quantitative polymerase chain reverse (RTqPCR), Western blot, histology, and ELISA. According to the statistical distribution of the data, specific tests will be used to compare the results. A significance level of p<0.05 will be adopted. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TAVARES, MARIA EDUARDA ALMEIDA; PINTO, ANA PAULA; DA ROCHA, ALISSON LUIZ; SAMPAIO, LARISSA VICTORINO; CORREIA, RAFAEL RIBEIRO; BATISTA, VICTOR ROGERIO GARCIA; VERAS, ALLICE SANTOS CRUZ; CHAVES-NETO, ANTONIO HERNANDES; DA SILVA, ADELINO SANCHEZ RAMOS; TEIXEIRA, GIOVANA RAMPAZZO. Combined physical exercise re-synchronizes expression of Bmal1 and REV-ERBα and up-regulates apoptosis and metabolism in the prostate during aging. Life Sciences, v. 351, p. 12-pg., 2024-06-17. (21/06291-3, 22/06807-2, 20/16310-2, 19/11820-5)