@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}
}