Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model

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.

Keywords: autophagy; biogenesis; brain dysfunction; mitochondrial dysfunction; sepsis.