@article{discovery10086125, year = {2019}, volume = {133}, number = {18}, title = {Mitochondria dysfunction is associated with long-term cognitive impairment in an animal sepsis mode}, note = {This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.}, publisher = {PORTLAND PRESS LTD}, month = {September}, pages = {1993--2004}, journal = {Clinical Science}, author = {Manfredini, A and Constantino, L and Pinto, MC and Michels, M and Burger, H and Kist, LW and Silva, MC and Gomes, LM and Dominguini, D and Steckert, A and Simioni, C and Bogo, M and Streck, E and Barichello, T and de Quevedo, J and Singer, M and Ritter, C and Dal-Pizzol, F}, url = {https://doi.org/10.1042/CS20190351}, 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.}, issn = {1470-8736}, keywords = {autophagy, biogenesis, brain dysfunction, mitochondrial dysfunction, sepsis} }