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The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m-amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After 30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m-amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)-1β, IL-6, IL-10, tumour necrosis factor-α, dopamine-cAMP-regulated phosphoprotein of 32,000 kDa (DARPP-32) and neuronal calcium sensor (NCS-1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain-derived neurotrophic factor (BDNF), neuronal growth factor and glial-derived neurotrophic factor levels were assessed in the hippocampus. M-amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m-amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk-like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m-amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M-amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M-amphetamine dose-dependently increased DARPP-32 and NCS-1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Sepsis-associated encephalopathy is highly prevalent and has impact both in early and late morbidity and mortality. The mechanisms by which sepsis induces brain dysfunction include neuroinflammation, disrupted blood-brain barrier, oxidative stress, and microglial activation, but the cellular and molecular mechanisms involved in these events are not completely understood. Our objective was to determine the effects of microglial depletion in the early systemic and brain inflammatory response and its impact in phenotypes expression in an animal model of sepsis. Animals were subjected to CLP, and depletion of microglial cells was accomplished by administration of (Lipo)-encapsulated clodronate and microglial repopulation by doxycycline. Clod-lip treatment was effective in decreasing microglia density in the hippocampus of animals. Pro-inflammatory cytokines were increased in the CLP+PBS, and liposomes administration increased even further these cytokines mainly 7 days, suggesting that microglial depletion exacerbates both local and systemic inflammation. In contrast, repopulation with doxycycline was able to revert the cytokine levels in both serum and cerebral structures on day 7 and 14 after repopulation. There were no differences in the correlation between M1 and M2 markers by real-time PCR, but immunohistochemistry showed significant increase in CD11b expression in CLP+PBS with greater expression in CLP + liposomes in the hippocampus. These results suggest that the depletion of microglia during severe sepsis development could be associated with early exacerbation of brain and systemic inflammation and repopulation is able to revert this condition, once a rapid neurological recovery is noticed until 7 days after sepsis.

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 . 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 Results: oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. 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., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Sepsis is systemic inflammatory response syndrome with a life-threatening organ dysfunction that is caused by an unbalanced host immune response in an attempt to eliminate invasive microorganisms. We posed questions, "Does sepsis survivor patients have increased risk of neuropsychiatric manifestations?" and "What is the mechanism by which sepsis induces long-term neurological sequelae, particularly substantial cognitive function decline in survivor patients and in pre-clinical sepsis models?" The studies were identified by searching PubMed/MEDLINE (National Library of Medicine), PsycINFO, EMBASE (Ovid), LILACS (Latin American and Caribbean Health Sciences Literature), IBECS (Bibliographical Index in Spanish in Health Sciences), and Web of Science databases for peer-reviewed journals that were published until January 2018. A total of 3555 papers were included in the primary screening. After that, 130 articles were selected for the study. A number of pre-clinical studies have shown an auto amplification of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in the first few hours after sepsis induction, also increased blood-brain barrier permeability, elevated levels of matrix metalloproteinases, increased levels of damage-associated molecular patterns were demonstrated. In addition, the rodents presented long-term cognitive impairment in different behavioral tasks that were prevented by blocking the mechanism of action of these inflammatory mediators. Clinical studies have showed that sepsis survivors presented increased bodily symptoms such as fatigue, pain, visual disturbances, gastrointestinal problems, and neuropsychiatric problems compared to before sepsis. Sepsis leaves the survivors with an aftermath of physiological, neuropsychiatric, and functional impairment. Systematic review registration: CRD42017071755.

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) are important for the maintenance of brain homeostasis. During sepsis, peripheral production of proinflammatory cytokines and reactive oxygen species are responsible for structural alterations in those brain barriers. Thus, an increasing permeability of these barriers can lead to the activation of glial cells such as microglia and the production of cytotoxic mediators which in turn act on the brain barriers, damaging them further. Thereby, in this review, we try to highlight how the brain barrier's permeability is not only a cause but a consequence of brain injury in sepsis.

Systemic inflammation is emerging as a significant driver of cognitive decline in the aged and vulnerable brain. In sepsis survivors animals low-grade brain inflammation occurs, suggesting that sepsis is able to induce in microglia a primed-like state. The purpose of this study is to analyze the role of sepsis-induced brain inflammation in the progression of the physiological process of brain aging. Wistar rats 2month-old were subjected to sepsis and 60 and 90days after were submitted to the new object recognition test and brain was removed to the determination of cytokines, myeloperoxidase (MPO) activity, amyloid-beta peptide (Aβ) and immunohistochemistry markers of microglial activation. In the hippocampus, from 60 to 90days there was an increase in TNF-α and IL-1β levels in septic animals. This also occurred to the levels of IL-1β and IL-6 in the prefrontal cortex. This was associated with persistent increased in microglial activation and Aβ levels. In conclusion, neuroinflammation is persistent after sepsis and this could burst the usual inflammation that occurs during brain aging., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that may affect the brain. We investigated the role of indoleamine 2,3-dioxygenase (IDO-1/2) inhibition on long-term memory and energetic metabolism after experimental sepsis by caecal ligation and perforation (CLP). Experimental sepsis increased the activity of complexes I, II-III and IV at 24h after CLP, and IDO-1/2 inhibition normalized the activity of these complexes in the hippocampus. Wistar rats presented impairment of habituation and aversive memories 10days after CLP. Adjuvant treatment with the IDO inhibitor prevented long-term cognitive impairment triggered by sepsis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

There are different theories about the pathophysiology of sepsis-associated encephalopathy (SAE), and the majority of our knowledge was derived from critically ill patients. 7In less severe sepsis, it is probable that neuroinflammation can be a major aspect of SAE development. We hypothesized that in non-severe septic patients, blood biomarkers of inflammation, endothelial activation, coagulation, and brain function would be different when compared to patients with and without brain dysfunction. A total of 30 patients presenting with community-acquired pneumonia (CAP)-induced sepsis were included of which 10 (33 %) developed SAE. Eight medical patients admitted to the general ward, except due to sepsis or infection, which developed delirium were included as delirium, non-sepsis group. From all measured biomarkers, only brain-derived neurotrophic factor (BDNF), regulated upon activation normal T cell expressed, and presumably secreted (RANTES), and interleukin (IL)-10 where significantly different when compared to SAE and sepsis groups. In addition, SAE patients presented higher levels of BDNF, vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-derived growth factor (PDGF)-AB/BB and RANTES when compared to delirium patients. In conclusion, the profile of biomarkers differs between SAE, sepsis, and delirium patients, suggesting that pathways related to SAE are different from delirium and from sepsis itself.

Epigenetic mechanisms are involved in normal behavior and are implicated in several brain neurodegenerative conditions, psychiatric and inflammatory diseases as well. Moreover, it has been demonstrated that sepsis lead to an imbalance in acetylation of histones and that histone deacetylase inhibitors (HDACi) can reverse this condition. In the present study, we evaluated the effects of a microinjection of sodium butyrate (SB, HDACi) into cerebral ventricle on aversive memory in rats submitted to the sepsis. Rats were given a single intraventricular injection of artificial cerebrospinal fluid (ACSF) or SB and immediately after the stereotaxic surgery and the drug infusion, the animals were subjected to cecal ligation and perforation (CLP). The animals were killed twenty four hours or ten days after sepsis induction and the prefrontal cortex, hippocampus, striatum and cortex were obtained to the determination of histone deacetylase activity. In a separate cohort of animals 10 days after sepsis induction, it was performed the inhibitory avoidance task. SB administration was able to reverse the impairment in aversive memory and inhibited the HDAC activity in prefrontal cortex and hippocampus 10 days after CLP. These support a role for an epigenetic mechanism in the long-term cognitive impairments observed in sepsis survivors animals., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study aimed to evaluate the effect of sepsis on behavioral changes on the ketamine-induced animal model of schizophrenia. Male Wistar rats underwent Cecal Ligation and Perporation (CLP) with "basic support" or were sham-operated. After 30 days, the animals were submitted to a model of schizophrenia by injection of Ketamine. The behavior tests were performed after 30 min of the injection of Ketamine or saline. Ketamine in doses of 15 and 25mg/kg increased locomotor activity, latency to first contact in the social interaction and stereotyped behavior. Some changes caused by sepsis may be associated with a predisposition to develop schizophrenia in the animal model., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.

Oxidative stress and inflammation is likely to be a major step in the development of sepsis-associated encephalopathy (SAE) and long-term cognitive impairment. To date, it is not known whether brain inflammation and oxidative damage are a direct consequence of systemic inflammation or whether these events are driven by brain resident cells, such as microglia. Therefore, the aim of this study is to evaluate the effect of minocycline on behavioral and neuroinflammatory parameters in rats submitted to sepsis. Male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP). The animals were divided into sham-operated (Sham+control), sham-operated plus minocycline (sham+MIN), CLP (CLP+control) and CLP plus minocycline (CLP+MIN) (100 μg/kg, administered as a single intracerebroventricular (ICV) injection). Some animals were killed 24h after surgery to assess the breakdown of the blood brain barrier, cytokine levels, oxidative damage to lipids (TBARS) and proteins in the hippocampus. Some animals were allowed to recover for 10 days when step-down inhibitory avoidance and open-field tasks were performed. Treatment with minocycline prevented an increase in markers of oxidative damage and inflammation in the hippocampus after sepsis. This was associated with an improvement in long-term cognitive performance. In conclusion, we demonstrated that the inhibition of the microglia by an ICV injection of minocycline was able to decrease acute brain oxidative damage and inflammation as well as long-term cognitive impairment in sepsis survivors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Studies have consistently reported the participation of oxidative stress, energetic metabolism impairment, and creatine kinase (CK) activity alterations in rat brain in early times in an animal model of sepsis and persist for up to 10 days. We have assessed the antioxidant effects of administration of Ebselen (Eb) e diphenyl diselenide (PhSe)2 two organoselenium compounds on brain oxidative stress, energetic metabolism, and CK activity 12, 24 h, and 10 days after sepsis by cecal ligation and perforation (CLP) in rats. Male Wistar rats underwent either sham operation or CLP and were treated with oral injection of Eb (50 mg/kg) or (PhSe)2 (50 mg/kg) or vehicle. 12, 24 h, and 10 days after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex, and cortex) were obtained and assayed for thiobarbituric acid reactive species and protein carbonyls formation, mitochondrial respiratory chain, and CK activity. We observed in the results a reduction of oxidative damage to lipids and proteins in the different cerebral structures studied and times with the administration of (PhSe)2; however, Eb seems to exert the same effect. Such changes are reflected in the assessment of mitochondrial respiratory chain complexes by reversing the decreased activity of the complex caused by the model of CLP and CK activity. Our data provide the first experimental demonstration that (PhSe)2 was able to reduce the brain dysfunction associated with CLP-induced sepsis in rats, by decreasing oxidative stress parameters mitochondrial dysfunction and CK activity in early times and in late time.

Sepsis is defined as the host's reaction to infection and it is characterized by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, disturbance of neurotransmitters, apoptosis, and cognitive impairment. It is known that during the process of learning and memory formation several pathways are involved such as dopaminergic and cholinergic systems. Thus, the objective of this study is to evaluate the neuronal calcium sensor (NCS-1) and dopamine-cAMP regulated phosphoprotein of 32,000 kDa (DARPP-32) expression as well as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in prefrontal cortex and hippocampus of rats 12, 24, and 48 h after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation procedure. After 12 and 24 h, there was an increase of NGF levels in hippocampus; and up to 48 h, a decrease of NCS-1 expression in prefrontal cortex, a decrease of BDNF levels in hippocampus and an increase of NGF levels in hippocampus. In conclusion, we believe that the low expression of NCS-1 in prefrontal cortex and low levels of BDNF in hippocampus may be associated with the pathophysiology of cognitive impairment during sepsis and a putative role of the dopaminergic system., (© 2014 Wiley Periodicals, Inc.)

Sepsis is defined as the host's reaction to infection and characterised by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, an imbalance of neurotransmitters, apoptosis and cognitive impairment. It's known that the IL-1β is one of the first cytokines to be altered. Thus, the objective of this study was to evaluate the role of IL-1β in cognitive parameters in brain tissue through the use of an IL-1β (IL-1ra) receptor antagonist up to 10 days and to assess blood-brain barrier permeability, cytokine levels, oxidative parameters and energetic metabolism up to 24 h, after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation (CLP) procedure. Immediately after, the animals received one dose of 10 μg of IL-1ra. After 24 h, the rats were killed and were evaluated for biochemical parameters in the pre-frontal cortex, hippocampus and striatum. After 10 days, the animals were submitted to the habituation to the open field and step-down inhibitory avoidance task. We observed that the use of IL-1ra reverted the increase of blood-brain barrier permeability in the pre-frontal cortex, hippocampus and striatum; the increase of IL-1β, IL1-6 and TNF-α levels in the pre-frontal cortex and striatum; the decrease of complex I activity in the pre-frontal, hippocampus and striatum; the increase of oxidative parameters in pre-frontal cortex, hippocampus and striatum; and cognitive impairment. In conclusion, the results observed in this study reinforce the role of acute brain inflammatory response, in particular, the IL1β response, in the cognitive impairment associated with sepsis.

Survivors from sepsis present long-term cognitive deficits and some of these alterations resemble the pathophysiological mechanisms of neurodegenerative diseases. For this reason, we analyzed beta-amyloid peptide (Aβ) and synaptophysin levels in the brain of rats that survived from sepsis and their relation to cognitive dysfunction and to acute brain inflammation. Sepsis was induced in rats by cecal ligation and puncture, and 30 days after surgery, the hippocampus and prefrontal cortex were isolated just after cognitive evaluation by the inhibitory avoidance test. The immunocontent of Aβ and synaptophysin were analyzed by Western blot analysis. Aβ increased and synaptophysin decreased in septic animals both in the hippocampus and prefrontal cortex concurrent with the presence of cognitive deficits. Prefrontal levels of synaptophysin correlated to the performance in the inhibitory avoidance. Two different treatments known to decrease brain inflammation and oxidative stress when administered at the acute phase of sepsis decreased Aβ levels both in the prefrontal cortex and hippocampus, increased synaptophysin levels only in the prefrontal cortex, and improved cognitive deficit in sepsis-survivor animals. In conclusion, we demonstrated that brain from sepsis-survivor animals presented an increase in Aβ content and a decrease in synaptophysin levels and cognitive impairment. These alterations can be prevented by treatments aimed to decrease acute brain inflammation and oxidative stress.

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., (Copyright © 2013 Wiley Periodicals, Inc.)

There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.

Oxidative damage and inflammation occur early in the brain after sepsis and are resolved when long-term cognitive impairment occurs. There is no information of a direct relation between acute levels of brain inflammation and oxidative damage and long-term cognitive deficits. We hypothesized that higher levels of early oxidative damage and inflammation are followed by long-term cognitive deficits, and this is related to a decrease in the levels of brain-derived neurotropic factor (BDNF). Wistar rats were subjected to sham operation or cecal ligation and perforation and the cerebrospinal fluid (CSF) was obtained 6 and 24 h after the determination of thiobarbituric acid-reactive species, interleukin 1 (IL-1), IL-10, and tumor necrosis factor α (TNF-α). Animals were followed until 30 days after surgery and were subjected to the step-down inhibitory avoidance (IA) task, and the hippocampus levels of BDNF were determined. At 6 h, higher CSF levels of thiobarbituric acid-reactive species and TNF-α were observed in septic animals that had a better performance in the IA task and presented higher BDNF levels in the hippocampus. At 24 h, higher CSF levels of IL-1β and TNF-α were observed in septic animals that had a worse performance in the IA task, and this was associated with lower BDNF levels. The persistence of brain inflammation during the acute phase of sepsis is associated with long-term hippocampus levels of BDNF and memory impairment in sepsis survivors.

The brain is one of the first organs affected during sepsis development resulting in apoptosis for a short-term and cognitive impairment for a long-term. Despite its importance, the mechanisms of brain dysfunction during sepsis are not fully elucidated. Thus, we here, in an animal model of sepsis, evaluated apoptosis in the dentate gyrus cell layer of the hippocampus to document the involvement of caspase-3 in the pathogenesis of neuronal apoptosis. Wistar rats sham-operated or submitted to the cecal ligation and perforation (CLP) procedure were killed at 12, 24, 48 h, and 10 days after surgery for the determination of caspase-3 and apoptosis rate. In a separate cohort of animals, a caspase-3-specific inhibitor was administered and animals were killed at 12 h after sepsis. An increase in the number of apoptotic cells 12, 24, and 48 h by histopathological evaluations and an increase of caspase-3 apoptotic cells 12 and 24 h after sepsis induction were observed. The caspase-3 inhibitor decreases the number of apoptotic cells by histopathological evaluations but not by immunohistochemistry evaluations. Caspase-3 is involved in part in apoptosis in the dentate gyrus cell layer of the hippocampus in septic rats submitted by CLP.

Sepsis is characterized by systemic biochemical alterations including the central nervous system in the early times and cognitive impairment at later times after sepsis induction in the animal model. Recent studies have shown that, besides its hematological activity, erythropoietin (EPO) has cytoprotective effects on various cells and tissues. In order to corroborate elucidating the effects of alternative drugs for sepsis treatment, we evaluated the effects of both acute and chronic EPO treatment on oxidative stress and energetic metabolism in the hippocampus, and cognitive impairment, respectively, after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with "basic support" or sham operation. In the acute treatment, EPO was administered once immediately after CLP induction. The rats were then killed after 6 and 24 h, and the hippocampus was removed for analysis of oxidative stress and energetic metabolism, respectively. Regarding the chronic treatment, EPO was administered once daily until the 4th day after induction. Aversive memory was tested on the 10th day after surgery. It was observed that the acute use of EPO (a single dose) alters the oxidative parameters and energetic metabolism. Chronic use (4 days) reversed cognitive impairment in the sepsis animal model. Mortality rates were attenuated only during chronic treatment.

The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effects of sepsis on brain microvasculature leukocyte rolling and adherence, myeloperoxidase (MPO) activity, cytokine and chemokine concentrations, and behavioral screening 6, 12, and 24 h after sepsis induction., Methods: C57BL/6 mice or Wistar rats underwent cecal ligation and perforation (CLP) or sham operation. At 6, 12, and 24 h after sepsis induction, intravital microscopy was performed in the mice brain microvasculature to evaluate leukocyte rolling and adherence. Animals were killed and had the brain removed to determine MPO activity and the levels of cytokines and chemokines. A behavioral screening was also performed in a separate cohort of animals. Blood-brain barrier (BBB) permeability and cytokines and chemokines were determined in different brain regions in Wistar rats., Results: There was a decrease in circulating leukocyte levels at 6, 12, and 24 h, an increase in rolling and adhesion of leukocytes in the brain microvasculature, followed by an increase in brain MPO activity. In addition, there was an increase in both brain cytokines and chemokines at different times. There was a decrease in the neuropsychiatric state muscle tone and strength only at 6 h, and a decrease in the autonomous function at 6 and 12 h. The pattern of brain cytokines and chemokines, and BBB permeability between the analyzed regions seemed to be similar with minor differences., Conclusions: During sepsis the brain's production of cytokines and chemokines is an early event and it seemed to participate both in central nervous system (CNS) dysfunction and BBB permeability alterations, reinforcing the role of brain inflammatory response in the acute CNS dysfunction associated with sepsis.

Sepsis is an infectious insult resulting in disturbances in the normal regulation of many organic systems, including the central nervous system. This study aims to evaluate aversive memory as well as its variances-posttraumatic memory and memory of extinction-in survivor rats submitted to sepsis by cecal ligation and perforation (CLP) at 10, 30, and 60 days after CLP, utilizing the inhibitory avoidance (IA) task paradigm. Male Wistar rats underwent either CLP or sham surgery under anesthesia. Sepsis group received antibiotics and fluid support, whereas sham group received only fluid replacement. The rats were divided in four different tasks: (1) aversive memory after 10, 30, and 60 days after CLP; (2) memory of extinction 60 days after CLP; (3) aversive memory-two trainings paradigm 10 days after CLP; and (4) posttraumatic memory 10 days after CLP. The aversive memory was impaired at 10, 30, but not 60 days after CLP, However, no damage was found in aversive memory after two training sessions. Additionally, there was no damage to the memory of extinction 60 days after CLP. Posttraumatic memory impairment was also observed. In this regard, we believe that our results provide relevant insights into the mechanisms involved in the cognitive deficits associated with sepsis.

Sepsis is characterized by biochemical alterations in the central nervous system at early times and cognitive impairment at late times after induction in sepsis animal model. In order to understand at least in part the mechanism of disease, we have evaluated the effects of sepsis on cytokine levels in the cerebrospinal fluid (CSF); oxidative parameters; the activity of the electron transport chain enzymes; and creatine kinase (CK) activity in the brain of sepsis survivor rats 10 days after cecal ligation and perforation (CLP). Male Wistar rats underwent CLP with "basic support" or sham-operated. Ten days after surgery, the animals were killed and prefrontal cortex, cortex, hippocampus, striatum, cerebellum, and CSF were obtained. It was found a decrease in the levels of TNF-α (P = 0.001), IL-1β (P = 0.008), IL-6 (P = 0.038), and IL-10 (P = 0.022) in the CSF; an increase in the TBARS only hippocampus (0.027); an up-regulation in the activity of complex II (P = 0.024), III (P = 0.018), and IV (P = 0.047) only in the prefrontal cortex; a decrease in the CK activity in the cerebellum (P = 0.001) and striatum (P = 0.0001), and an increase in the hippocampus (P = 0.0001) and cortex (P = 0.0001). Oxidative stress and mitochondrial alterations observed during early times in sepsis, persisted up to 10 days after surgery. The cytokines levels during the early times were found at high levels, decreasing to low levels after 10 days. In conclusion, these findings may contribute for a better comprehension of the cognitive damage in sepsis survivor rats.

Oxidative stress plays an important role in the development of cognitive impairment in sepsis. Here we assess the effects of acute and extended administration of cannabidiol (CBD) on oxidative stress parameters in peripheral organs and in the brain, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent either sham operation or CLP. Rats subjected to CLP were treated by intraperitoneal injection with "basic support" and CBD (at 2.5, 5, or 10mg/kg once or daily for 9days after CLP) or vehicle. Six hours after CLP (early times), the rats were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus, striatum, and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day (late times), the rats were submitted to the inhibitory avoidance task. After the test, the animals were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus) were obtained and assayed for TBARS formation and protein carbonyls. The acute and extended administration of CBD at different doses reduced TBARS and carbonyl levels in some organs and had no effects in others, ameliorated cognitive impairment, and significantly reduced mortality in rats submitted to CLP. Our data provide the first experimental demonstration that CBD reduces the consequences of sepsis induced by CLP in rats, by decreasing oxidative stress in peripheral organs and in the brain, improving impaired cognitive function, and decreasing mortality., (Copyright 2010 Elsevier B.V. All rights reserved.)

Sepsis is characterized by a systemic inflammatory response of the immune system against an infection, presenting with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, behavior alterations, and high mortality. In this study, we aimed to evaluate the effects of dexamethasone on mortality, anhedonia, circulating corticosterone and adrenocorticotropin hormone (ACTH) levels, body and adrenal gland weight, and aversive memory in sepsis survivor rats. Male Wistar rats underwent sham operation or cecal ligation and perforation (CLP) procedure. Rats subjected to CLP were treated with "basic support" and dexamethasone (at 0.2 and 2mg/kg daily for 7 days after CLP, intraperitonially) or saline. After 10 days of sepsis procedure, it was evaluated aversive memory, sweet food consumption, and body and adrenal gland weight. Serum and plasma were also obtained. It was observed that low dose dexamethasone reverted anhedonia, normalized adrenal gland and body weight, corticosterone and ACTH levels, and decreased mortality and avoidance memory impairment, demonstrating that low doses of dexamethasone for moderate periods may be beneficial for sepsis treatment and its sequelae-depressive-like parameters and memory impairment.

The inflammatory and immune responses evoked in sepsis may create not only an acute brain dysfunction, which occurs in the majority of septic patients, but also long-term deficits such as memory impairment. In this context, we evaluated depressive-like parameters in sepsis survivor rats. For this purpose, male Wistar rats, weighing 300-350 g, underwent cecal ligation and perforation (CLP) (sepsis group) followed by "basic support", or were sham-operated (control group). After 3 days of the sepsis procedure, the animals were treated with imipramine at 10 mg/kg or saline during 14 days (days 3-17). The consumption of sweet food was measured for 7 days (days 10-17) and the body weight was measured before CLP, 10, and 17 days after CLP. Seventeen days after sepsis (immediately after sweet food consumption measurement), the animals were anesthetized and blood was withdrawn for the analyses of corticosterone and adrenocorticotropic hormone (ACTH) levels, and immediately killed by decapitation. The adrenal gland and hippocampus were immediately isolated and weighed, and the hippocampus was utilized for determining brain-derived neurotrophic factor (BDNF) levels. It was observed that animals subjected to CLP presented decreased sucrose intake. Septic rats did not increase body weight and presented an increase in the weight of adrenal gland. Both corticosterone and ACTH levels were increased, while hippocampus weight and BDNF levels in the hippocampus decreased. The treatment with imipramine reversed all the parameters described above. Our results supported the hypothesis that rats that survive sepsis show depressive-like behavior, alterations in the hypothalamus-pituitary-adrenal axis, and decreased BDNF levels in the hippocampus.

Background: The aim of this study was to examine the effects of the N-methyl-D-aspartate receptor (NMDAR) channel blocker dizocilpine (MK-801) on lung injury in rats submitted to experimental sepsis induced by cecal ligation and perforation (CLP)., Methods: Adult male Wistar rats submitted to CLP were given a single systemic injection of MK-801 (subcutaneously at 0.3 mg/kg) administered 4 or 7 h after CLP induction. Twelve hours after CLP BAL was performed to determine total cell count, protein content, and inflammatory parameters. In addition, lung was excised for histopathologic analyses and determination of NMDAR subunits content. In a separate cohort of animals mortality was recorded for 5 days., Results: Animals submitted to sepsis induced by CLP showed an increase in the content of NMDAR subunits NR1 and NR2A in the lung. Administration of MK-801 4 h after CLP induction resulted in a decrease in BAL fluid cellular content and decreased levels of proinflammatory cytokines. In addition, MK-801 decreased lung oxidative stress markers and histopathologic alterations and improved survival., Conclusions: These findings indicate that NMDAR blockade might represent a promising novel therapeutic strategy for the treatment of sepsis and inflammatory disorders.

Oxidative stress has drawn a lot of attention in the past few decades, since it has been reported to participate in the mechanism of many diseases. Therefore, it seemed to be a good rationale to aim oxidative stress on therapeutic research. Sepsis is a complex systemic syndrome characterized by an imbalance between pro- and anti-inflammatory responses to a pathogen; its pathophysiology is a dynamic process which involves components of the immune system, the coagulation pathway, parenchymal cells, and the endocrine and metabolic pathways. It is well characterized that oxidative stress plays a crucial role in sepsis development, but the relation between central nervous system dysfunction and oxidative stress during sepsis is not well understood. Thus, we here summarize the current knowledge on the role of free radicals in the development of brain dysfunction in sepsis focusing on oxidative damage and the redox control of brain inflammatory pathways.

The objective of this study was to evaluate the rivastigmine effect on habituation to the open-field memory impairment observed in sepsis survivor rats. A prospective, controlled experiment was designed. The setting was an animal basic science laboratory, and the subjects were male Wistar rats weighing 300 to 350 g. Rats underwent cecal ligation and puncture (CLP; sepsis group) with "basic support" (saline at 50 mL kg(-1) immediately and 12 h after CLP plus ceftriaxone at 30 mg kg(-1) and clindamycin at 25 mg kg(-1) 6, 12, and 18 h after CLP) or sham-operated (control group). Three days after surgery (1 week before the start the behavior procedure), treatment with rivastigmine was started. Ten days after surgery, animals were submitted to the habituation to an open-field memory test. In the test session, there was a significant reduction in both crossings and rearings in the sham and sepsis group that received rivastigmine when compared with the training, indicating memory acquisition. In contrast, in the sepsis group that did not receive rivastigmine there was no difference in crossings and rearings between training and test session, indicating an impairment in memory acquisition. Therefore, rivastigmine reversed cognitive impairment in sepsis survivor rats in the open-field test.

Sepsis is a major disease entity with important clinical implications. It is associated with a high mortality rate in humans. Recently, several studies have demonstrated that Intensive Care Unit survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. The pathogenesis of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. Here we discuss the clinical presentation and underlying pathophysiology of the encephalopathy and neurobiology of the cognitive impairment associated with sepsis.

We here evaluated the central dopaminergic response in sepsis survivor rats using the administration of D-amphetamine. Male Wistar rats underwent cecal ligation and perforation (CLP) or were sham-operated. After 10 days of recovery, rats received an intraperitoneal injection of D-amphetamine 0.5, 1 and 2 mg/kg or saline, and were subjected to the open field test. We did not observe alterations in locomotor and exploratory activities in CLP compared to sham group. Treatment with amphetamine 0.5 mg/kg did not have effect in sham and CLP groups; D-amphetamine 1 mg/kg increased locomotor and exploratory activities only in sham group, and D-amphetamine 2 mg/kg increased in both sham and CLP groups. We suggest that, in part, dopamine pathway may be altered in sepsis.

Sepsis is a major disease entity with important clinical implications. Sepsis-induced multiple organ failure is associated with a high mortality rate in humans and is clinically characterized by pulmonary, cardiovascular, renal and gastrointestinal dysfunction. Recently, several studies have demonstrated that sepsis survivors present long-term cognitive impairment, including alterations in memory, attention, concentration and/or global loss of cognitive function. However, the pathogenesis and natural history of septic encephalopathy and cognitive impairment are still poorly known and further understanding of these processes is necessary for the development of effective preventive and therapeutic interventions. This review discusses the clinical presentation and underlying pathophysiology of the encephalopathy and cognitive impairment associated with sepsis.

Objective: To evaluate the cognitive performance in rats that survived sepsis induced by cecal ligation and puncture (CLP) after 10, 30 and 60 days., Design: Prospective, controlled experiment., Setting: Animal basic science laboratory., Subjects: Male Wistar rats, weighing 300-350 g., Interventions: The rats were sham-operated or submitted to CLP (sepsis group) with "basic support" (saline, s.c. at 50 mL/kg immediately and 12 h after CLP plus ceftriaxone, s.c. at 30 mg/kg and clindamycin, s.c. at 25 mg/kg 6, 12 and 18 h after CLP)., Measurements and Main Results: The animals underwent six behavioral tasks 10, 30 and 60 days after surgery: (a) habituation to the open field; (b) inhibitory avoidance task; (c) continuous multiple trials step-down inhibitory avoidance task; (d) object recognition; (e) elevated plus-maze; and (f) forced swimming test. We demonstrated that survivors 10 days after CLP presented deficits on the habituation to the open field, step-down inhibitory avoidance, continuous multiple-trials step-down inhibitory avoidance, object recognition and forced swimming. After 30 days of sepsis induction, survivors maintained deficits on the step-down inhibitory avoidance, continuous multiple-trials step-down inhibitory avoidance and forced swimming. However, after 60 days all behavior deficits were reversed., Conclusions: These results indicate that the impairment of memory and learning, demonstrated 10 days after the induction of sepsis, persist 30 days after the CLP. The cognitive impairments did not persist after 60 days suggesting that this model can help in the understanding of the biological mechanisms associated with sepsis-induced sickness behavior.

The mechanisms responsible to the development of brain dysfunction during sepsis are not well understood. The objective of this study is to evaluate mitochondrial respiratory chain and creatine kinase activities in the brain after cecal ligation and perforation (CLP) in rats. We performed a prospective, controlled experiment in male Wistar rats. Rats were subjected to CLP (sepsis group) with saline resuscitation (at 50mL/kg immediately and 12h after cecal ligation and perforation) or sham operation (control group). Several times (0, 6, 12, 24, 48 and 96h) after CLP six rats were killed by decapitation, and brain structures (cerebellum, hippocampus, striatum and cortex) were isolated. Mitochondrial respiratory chain and creatine kinase activity were then measured. It was observed that animals submitted to CLP presented decreased mitochondrial respiratory chain activity in complex I, but not in complex II, III and IV, 24, 48 and 96h in all analyzed structures. Activity of succinate dehydrogenase was decreased in 48 and 96h in all analyzed structures. Creatine kinase activity increased after CLP in cerebellum, hippocampus and cortex (after 0h) and striatum (after 6h). Sepsis associated brain injury may include dysfunction in the mitochondrial respiratory chain activity.

Introduction: Survivors from sepsis have presented with long-term cognitive impairment, including alterations in memory, attention, concentration, and global loss of cognitive function. Thus, we evaluated the effects of memory enhancers in sepsis-surviving rats., Methods: The rats underwent cecal ligation and perforation (CLP) (sepsis group) with 'basic support' (saline at 50 mL/kg immediately and 12 hours after CLP plus ceftriaxone at 30 mg/kg and clindamycin at 25 mg/kg 6, 12, and 18 hours after CLP) or sham-operated (control group). After 10 or 30 days, rats were submitted to an inhibitory avoidance task. After task training, animals received injections of saline, epinephrine, naloxone, dexamethasone, or glucose. Twenty-four hours afterwards, animals were submitted to the inhibitory avoidance test., Results: We demonstrated that memory enhancers reversed impairment in the sepsis group 10 and 30 days after sepsis induction. This effect was of lower magnitude when compared with sham animals 10 days, but not 30 days, after sepsis., Conclusions: Using different pharmacologic approaches, we conclude that the adrenergic memory formation pathways are responsive in sepsis-surviving animals.

Objective: To evaluate the antidepressant effect of imipramine on depressive symptoms observed in sepsis survivors rats., Design and Setting: Prospective, controlled experiment in an animal basic science laboratory., Subjects: Male Wistar rats weighing 300-350 g., Interventions: The rats underwent cecal ligation and perforation (CLP; sepsis group) with "basic support" (saline at 50 ml/kg immediately and 12 h after CLP plus ceftriaxone at 30 mg/kg and clindamycin at 25 mg/kg 6, 12, and 18 h after CLP) or sham-operated (control group). After 10 days of recovery rats received intraperitoneal injections of imipramine 10 mg/kg or saline and were subjected to the forced swimming test., Measurements and Results: The observed increase in the immobility time in the forced swimming test in animals subjected to CLP, as a parameter of depressive behavior, was reversed by imipramine., Conclusions: The depressive symptoms evaluated by forced swimming test had been reversed after imipramine administration. Our data provide evidence that CLP-induced depressive symptoms are sensitive to antidepressants.

Objective: Assess the effect of antioxidant treatment on late memory impairment and early hippocampus oxidative stress after cecal ligation and perforation., Subjects: Male Wistar rats., Interventions: Rats underwent sham operation or cecal ligation and perforation. Animals that underwent cecal ligation and perforation were divided into groups: 1) treated with basic support (50 mL/kg saline, 30 mg/kg ceftriaxone, and 25 mg/kg clindamycin every 6 hrs), 2) treated with basic support plus N-acetylcysteine (20 mg/kg N-acetylcysteine at 3, 6, 12, 18, and 24 hrs after cecal ligation and perforation), 3) treated with basic support plus deferoxamine (20 mg/kg deferoxamine at 3 and 24 hrs after cecal ligation and perforation), 4) treated with basic support plus N-acetylcysteine and deferoxamine, or 5) treated with N-acetylcysteine plus deferoxamine., Measurements and Main Results: On days 10 and 30 after surgery, the animals underwent behavioral tasks: inhibitory avoidance task, habituation to an open field, and continuous multiple-trials step-down inhibitory avoidance task. The sepsis group showed significantly decreased performance in latency retention compared with the sham group in the inhibitory avoidance task. In the open-field task, the sepsis group presented memory impairment after sepsis. In the continuous multiple-trials step-down inhibitory avoidance task, the sepsis group showed a significant increase in the number of training trials required to reach the acquisition criterion. All these memory impairments were prevented by N-acetylcysteine plus deferoxamine treatment, but not its isolate use. In addition, the combined use of antioxidants attenuated oxidative damage in hippocampus 6 hrs after sepsis induction., Conclusions: Antioxidant treatment prevented the development of late cognitive deficits in an animal model of sepsis.

Central nervous system dopaminergic mechanisms have been implicated in the cytokine response to stress and sepsis. We here describe the effects of haloperidol or clozapine in the treatment of sepsis induced by cecal ligation and puncture. Male Wistar rats were subjected to the CLP procedure were treated with haloperidol or clozapine and plasma cytokines, myeloperoxidase activity, markers of organ injury and survival was analyzed. The addition of haloperidol or clozapine to basic support did not diminished hepatic, renal, pancreatic or muscular damage observed after sepsis. Neither haloperidol, nor clozapine, modulates pro and antiinflammatory cytokines after sepsis induction. In addition, haloperidol treatment did not diminished myeloperoxidase activity in the kidney, lung or liver, or altered BALF markers of lung damage or inflammatory infiltration. Our data did not support a role of haloperidol or clozapine as an immunomodulator agent in the treatment of sepsis in an animal model of peritonitis.

Objective: The underlying mechanisms of the changes in mental status, septic encephalopathy, and long-term cognitive symptoms in sepsis survivors have only been defined in part. The present study was undertaken to assess different variables of oxidative stress in several brain structures after cecal ligation and perforation in the rat., Design: Prospective animal study., Setting: Animal basic science laboratory., Subjects: Male Wistar rats, weighing 250-350 g., Interventions: Rats were subjected to cecal ligation and perforation (sepsis group) with saline resuscitation (at 50 mL/kg immediately and 12 hrs after cecal ligation and perforation) or sham operation (control group)., Measurements and Main Results: Oxidative damage, assessed by the thiobarbituric acid reactive species and the protein carbonyl assays, occurred early (after 6 hrs) in the course of sepsis development in the hippocampus, cerebellum, and cortex. At longer times after sepsis induction (12-96 hrs), there was no evidence of oxidative damage in all analyzed structures. Except for the striatum, earlier in sepsis development (6 hrs) we demonstrated an increase in superoxide dismutase activity without a proportional increase in catalase activity with a consequent increase in the relation of superoxide dismutase/catalase. The balance between these enzymes was restored in the studied structures 12-96 hrs after sepsis induction., Conclusions: The short-term oxidative damage demonstrated here could participate in the development of central nervous system symptoms during sepsis development, or even septic encephalopathy. The alterations in the superoxide dismutase/catalase relation were temporally related to the occurrence or not of oxidative damage in the central nervous system.

Highlights • Sepsis induced an anxious phenotype and memory impairment ten days after induction. • CHF or CLF did not modulate the long-term effect of sepsis. • Previous stress caused by CHF and CLF did not worse long-term cognitive impairment in septic survivors. Abstract Background Many sepsis survivor patients develop psychological problems and cognitive impairment. We hypothesize that previous stress exacerbate the cognitive impairment and anxiety in sepsis survivors. To test our hyphothesis, experimental animals that were selectively bred for high and low contextual fear conditioning were subjected to sepsis to evaluate long-term behavior changes. Methods Adult male Albino Wistar rats selectively bred for high (Carioca high-conditioned freezing - CHF) levels or low (Carioca low-conditioned freezing - CLF) levels of emotionality were subject to sepsis by the cecal ligation and perforation (CLP) or sham operated (no-CLP) as a control group. Elevated plus-maze and inhibitory avoidance tasks were performed 10 days after CLP and non-CLP surgeries. Results The sepsis survivor rats (wild-type, CHF, and CLF groups) and sham (CHF and CLF groups) presented anxious-like behavior evaluated by elevated plus-maze task. However, only sepsis groups presented aversive memory impairment evaluated by inhibitory avoidance task at 10 days after CLP surgery. The CLF or CHF did not interefere in the long-term impairment triggered by sepsis. Conclusion Our data suggest that previous stress did not interfere in the long-term cognitive impairment and anxious-like behavior observed in septic survivor rats. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen-associated molecular patterns (PAMP) and they are identified by pattern-recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of αβ-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-β peptide (Aβ) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aβ and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aβ and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Recent evidence suggests that peripheral markers related to oxidative stress, inflammation and neurotrophins may be altered during mood episodes in bipolar disorder. These can be seen as proxies of peripheral toxicity or markers of illness activity. Here we report an en bloc assessment of a set of previously described biomarkers in different mood states (n = 60) as well as in healthy subjects (n = 80). To make the point that these are ominous changes, we obtained the same measures from a group of septic patients (n = 15) as a “positive” control group. In this sample, we measured serum levels of brain derived neurotrophic factor, neurotrophin 3, tumor necrosis factor α, interleukin 6, interleukin 10, total reactive antioxidant potential, thiobarbituric acid reactive substances and protein carbonyl content. Several of the markers discriminated between the bipolar and control groups, especially when patients were in acute episodes. In some cases, toxicity was as high in bipolar disorder as that seen in patients with sepsis. We believe these findings highlight the potential of using biomarkers to assess illness activity in bipolar disorder. [ABSTRACT FROM AUTHOR]