Late brain alterations in sepsis‐survivor rats

Abstract

Central nervous system (CNS) dysfunction secondary to sepsis is characterized by long-term cognitive impairment. It was observed that oxidative damage, energetic metabolism impairment, and cytokine level alteration seen in early times in an animal model of sepsis may persist for up to 10 days and might be associated with cognitive damage. In order to understand these mechanisms, at least in part, we evaluated the effects of sepsis on cytokine levels in the cerebrospinal fluid (CSF), oxidative parameters, and energetic metabolism in the brain of rats at both 30 and 60 days after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with "basic support" or were sham-operated. Both 30 and 60 days after surgery, the CSF was collected and the animals were killed by decapitation. Then, the prefrontal cortex, hippocampus, striatum, and cortex were collected. Thirty days after surgery, an increase of IL-6 level in the CSF; an increase in the thiobarbituric acid-reactive species (TBARS) in prefrontal cortex and a decrease in hippocampus, striatum, and cortex; a decrease of carbonyl protein formation only in prefrontal cortex and an increase in striatum; and an increase in the complex IV activity only in hippocampus were observed. Sixty days after sepsis, an increase of TNF-α level in the CSF; a decrease of TBARS only in hippocampus; an increase of carbonyl protein formation in striatum; and a decrease of complex I activity in prefrontal cortex, hippocampus, and striatum were observed. These findings may contribute to understanding the role of late cognitive impairment. Further studies may address how these findings interact during sepsis development and contribute to CNS dysfunction.

Translational evidence for two distinct patterns of neuroaxonal injury in sepsis: a longitudinal, prospective translational study

“…The present translational study was performed to demonstrate evidence of axonal injury in the septic brains of animals and humans. Previous animal studies offer some evidence for different pathologic mechanisms of septic brain injury and behavioral changes [ 8 – 10 , 12 , 14 , 39 ]. The histologic findings in the rat brains in the present study suggest two major mechanisms of injury.…”

“…Current understanding of pathophysiological mechanisms of SAE is limited; more insights into this important field are needed [ 6 , 7 ]. Animal models can shed some light on the complex pathophysiological mechanisms of SAE [ 8 – 10 ]. Microglial activation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal apoptosis are potential risk factors for SAE, resulting in axonal degeneration [ 11 – 13 ].…”

Sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in surviving septic mice

“…Survivors especially suffer from sepsis-related brain dysfunction, which occurs in 8–70% of septic patients and is a common feature of sepsis[ 6 , 7 , 8 , 9 ]. The possible mechanisms of sepsis-related brain dysfunction include neuroinflammation, impaired cerebral microcirculation, oxidative stress, excitotoxicity, and blood-brain-barrier dysfunction[ 6 , 10 , 11 , 12 , 13 ]. However, the molecular mechanisms of sepsis-related brain dysfunction remain unclear.…”

CD40-CD40 Ligand Pathway Is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis

“…We consistently demonstrated that survivors from this model had several different cognitive deficits 10 d after CLP (29). Thus, it was determined that anti-CD40 was able to improve long-term cognitive impairment.…”