Consequences of the Lack of TNFR1 in Ouabain Response in the Hippocampus of C57BL/6J Mice
Paula Fernanda Kinoshita,
Ana Maria Orellana,
Diana Zukas Andreotti,
Giovanna Araujo de Souza,
Natalia Prudente de Mello,
Larissa de Sá Lima,
Elisa Mitiko Kawamoto,
Cristoforo Scavone
Affiliations
Paula Fernanda Kinoshita
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Ana Maria Orellana
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Diana Zukas Andreotti
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Giovanna Araujo de Souza
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Natalia Prudente de Mello
Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Larissa de Sá Lima
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Elisa Mitiko Kawamoto
Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Cristoforo Scavone
Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil
Ouabain is a cardiac glycoside that has a protective effect against neuroinflammation at low doses through Na+/K+-ATPase signaling and that can activate tumor necrosis factor (TNF) in the brain. TNF plays an essential role in neuroinflammation and regulates glutamate receptors by acting on two different receptors (tumor necrosis factor receptor 1 [TNFR1] and TNFR2) that have distinct functions and expression. The activation of constitutively and ubiquitously expressed TNFR1 leads to the expression of pro-inflammatory cytokines. Thus, this study aimed to elucidate the effects of ouabain in a TNFR1 knockout (KO) mouse model. Interestingly, the hippocampus of TNFR1 KO mice showed a basal increase in both TNFR2 membrane expression and brain-derived neurotrophic factor (BDNF) release, suggesting a compensatory mechanism. Moreover, ouabain activated TNF-α-converting enzyme/a disintegrin and metalloprotease 17 (TACE/ADAM17), decreased N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A) expression, and induced anxiety-like behavior in both genotype animals, independent of the presence of TNFR1. However, ouabain induced an increase in interleukin (IL)-1β in the hippocampus, a decrease in IL-6 in serum, and an increase in NMDA receptor subunit 1 (NR1) only in wild-type (WT) mice, indicating that TNFR1 or TNFR2 expression may be important for some effects of ouabain. Collectively, our results indicate a connection between ouabain signaling and TNFR1, with the effect of ouabain partially dependent on TNFR1.
