Andressa Manfredini1, Larissa Constantino1, Milton Castro Pinto1, Monique Michels1, Henrique Burger1, Luiza W Kist2,3, Milena Carvalho Silva4, Lara Mezzari Gomes4, Diogo Dominguini1, Amanda Steckert1, Carmen Simioni5, Mauricio Bogo2,3, Emílio Streck4, Tatiana Barichello6,7,8, João de Quevedo6,7,9,10, Mervyn Singer11, Cristiane Ritter1, Felipe Dal-Pizzol12. 1. Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil. 2. Genomics and Molecular Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil. 3. Postgraduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil. 4. Laboratory of Bioenergetics, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil. 5. Plant Cell Biology Laboratory, Department of Cell Biology, Embryology and Genetics, Federal University of Santa Catarina, Florianópolis, Brazil. 6. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, U.S.A. 7. Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, U.S.A. 8. Laboratory of Experimental Microbiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil. 9. Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, U.S.A. 10. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil. 11. Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom. 12. Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil fdpizzol@gmail.com.
Abstract
Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis. Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7-9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function. Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.
Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis. Methods:Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7-9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function. Results:Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.