The interleukin-6/kynurenine pathway in the hippocampus and its relationship with inflammation, apoptosis, and cognitive and behavioral disorders in excessive exercise condition in mice

• Grant number: 22/08930-6
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2023
• End date: April 30, 2025
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Rodrigo Pauli
• Grantee: José Rodrigo Pauli
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated researchers: Adelino Sanchez Ramos da Silva ; Dennys Esper Corrêa Cintra ; Eduardo Rochete Ropelle

Abstract

Overtraining syndrome is characterized by an imbalance between the recovery and training phases. Consequently, there may be a decline in performance and cognitive and behavioral disorders. Increases in pro-inflammatory cytokines are also notorious in this condition of over-training. The increase in interleukin-6 (IL-6) has been linked to the development of depressive signs. Intriguingly, it has been shown that the kynurenine (KYN) pathway can be activated by IL-6 with neurotoxic and harmful effects on the central nervous system (CNS). Thus, the increase in IL-6 caused by excessive physical exercise would be crucial to causing changes in the KYN pathway and hippocampus that would be associated with cognitive and behavioral disorders. Although relevant, investigations involving the hippocampal IL-6/KYN pathway in conditions of excessive physical exercise have still been poorly explored. Thus, the present research proposal aims to investigate the relationship between IL-6 and the KYN pathway in the hippocampus and the cognitive and behavioral alterations in mice submitted to excessive training. Wild Type (WT) and IL-6 knockout (IL-6-/-) mice will be used. These rodents will be submitted to the excessive physical exercise protocol. In addition, a group of WT mice will receive intracerebroventricular (ICV) administration of IL-6. Another group of animals will receive ICV administration of the pharmacological inhibitor of the KYN pathway (KMO) through implantation of the mini-osmotic pump and then they will be submitted to the protocol of excessive physical exercise. The mice will be submitted to cognitive and behavioral tests after the period of excessive physical exercise and other experimental tests. In addition, the hippocampus extracted from mice in the different experimental stages will be submitted to Western blot, RTqPCR, histology, and ELISA analyses. These data will allow an advance in the understanding of the mechanisms related to the cognitive imbalance related to excessive physical exercise and the relationship between the IL-6/KYN pathway in inflammation, apoptosis, and neurogenesis processes in the hippocampus of mice. (AU)