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.

Qiang Xin 1 Formula Suppresses Excessive Pro-inflammatory Cytokine Responses and Microglia Activation to Prevent Cognitive Impairment and Emotional Dysfunctions in Experimental Sepsis

“…Cognitive impairment was found in 25% of sepsis patients at 1 year after hospital discharge [28], and in about 70% at 1 year after ICU discharge [29]. Consistent with our results, animal studies using a CLP model reported cognitive and emotional dysfunction at day 10 after surgery [30,31]. A series of behavioral tests were carried out in our study, and it was noteworthy that the QX1 formula significantly reduced overall hippocampus-regulated learning and memory impairment detected by MWM and NORT, frontal cortex-regulated anxiety-like behaviors detected by OPT and EPM, and increased exploratory activity revealed by NORT and OFT, comprehensively demonstrated the neuroprotective effects of QX1 formula on behavior changes.…”

Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities

“…Sepsis survivors have a reduced hippocampal volume [49] and evidence of blood brain barrier (BBB) breakdown, as detected using magnetic resonance imaging (MRI) [ 50 ]. Murine sepsis survivors have increased rates of apoptosis in hippocampal neurons, [51] increased BBB permeability, [52] and ATP depletion [ 53 ]. The occurrence of delirium in sepsis is strongly associated with long-term cognitive issues [ 54 ].…”

“…Additionally, cerebral ischemia due to hypotension, hypoxia, and microvascular occlusion due to disseminated intravascular coagulation can cause damage, with one in three sepsis patients having (multiple) cerebral infarctions [ 62 ]. Glucose and oxygen deprivation from these infarctions leads to mitochondrial dysfunction and oxidative damage, [63] which results in neuronal apoptosis and cognitive dysfunction in septic rats [ 53 ]. Inducing mitochondrial biogenesis to increase mitochondrial mass improves cerebral ATP levels and cognition [ 53 ].…”

“…Glucose and oxygen deprivation from these infarctions leads to mitochondrial dysfunction and oxidative damage, [63] which results in neuronal apoptosis and cognitive dysfunction in septic rats [ 53 ]. Inducing mitochondrial biogenesis to increase mitochondrial mass improves cerebral ATP levels and cognition [ 53 ]. Consequently, therapies aimed at preserving cerebral mitochondrial homeostasis may prevent cognitive impairment post-sepsis.…”

Association of Mitochondrial Respiratory Chain Enzymes with the Risk and Mortality of Sepsis Among Chinese Children

“…Mitochondrial dysfunction is a feature of many pathologies, including sepsis [8][9][10]. Recent studies have shown that mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis [11].…”