Manfredini, A;
Constantino, L;
Pinto, MC;
Michels, M;
Burger, H;
Kist, LW;
Silva, MC;
... Dal-Pizzol, F; + view all
(2019)
Mitochondria dysfunction is associated with long-term cognitive impairment in an animal sepsis mode.
Clinical Science
, 133
(18)
pp. 1993-2004.
10.1042/CS20190351.
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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.
| Type: | Article |
|---|---|
| Title: | Mitochondria dysfunction is associated with long-term cognitive impairment in an animal sepsis mode |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1042/CS20190351 |
| Publisher version: | https://doi.org/10.1042/CS20190351 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | autophagy, biogenesis, brain dysfunction, mitochondrial dysfunction, sepsis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10086125 |
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