Manfredini 2019 Clin Sci (Lond)
|Manfredini A, Constantino L, Pinto MC, Michels M, Burger H, Kist LW, Silva MC, Gomes LM, Dominguini D, Steckert A, Simioni C, Bogo M, Streck E, Barichello T, de Quevedo J, Singer M, Ritter C, Dal-Pizzol F (2019) Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model. Clin Sci (Lond) 133:1993-2004.|
Manfredini A, Constantino L, Pinto MC, Michels M, Burger H, Kist LW, Silva MC, Gomes LM, Dominguini D, Steckert A, Simioni C, Bogo M, Streck E, Barichello T, de Quevedo J, Singer M, Ritter C, Dal-Pizzol F (2019) Clin Sci (Lond)
Abstract: 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.
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.
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.
Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Labels: MiParea: Respiration Pathology: Sepsis
Organism: Rat Tissue;cell: Nervous system Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS Pathway: N, NS HRR: Oxygraph-2k