Sepsis after middle cerebral artery occlusion exacerbates peripheral oxidative stress in a sex-specific manner.

Ischemic stroke occurs due a blockage in the blood flow to the brain, leading to damage to the nervous system. The prevalent morbidities resulting from stroke include post-stroke infection, as sepsis. Additionally, oxidative stress is recognized for inducing functional deficits in peripheral organs during sepsis. Therefore, sex differences in stroke exist and we aimed to investigate the peripheral oxidative stress caused by sepsis after stroke in male and female rats. Wistar rats (male and female) were divided into sham+sham, middle cerebral artery occlusion (MCAO) + sham, sham+ cecal ligation and perforation (CLP) and MCAO+CLP groups to males and female rats. Animals were subjected to MCAO or sham and after 7 days, were subjected to sepsis by CLP or sham. After 24 h, serum, total brain, lung, liver, heart, and spleen were collected. Brain edema, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, oxidative damage to lipids and proteins, and catalase activity were evaluated. Brain edema was observed only in male rats in MCAO+CLP group compared to MCAO+sham. Regarding MPO activity, an increase was verified in male in different organs and serum in MCAO+CLP group. For N/N levels, the increase was more pronounced in females submitted to MCAO+CLP. In general, to oxidative stress, an increase was only observed in animals exposed to MCAO+CLP, or with a greater increase in this group compared to the others. The findings provided the first indication that animals exposed to MCAO exhibit a heightened vulnerability to the harmful impacts of sepsis, as evidenced by brain edema and peripheral oxidative stress, and this susceptibility is dependent of sex.

Sepsis compromises post-ischemic stroke neurological recovery and is associated with sex differences.

AIMS: Infection is a complication after stroke and outcomes vary by sex. Thus, we investigated if sepsis affects brain from ischemic stroke and sex involvement. MAIN METHODS: Male and female Wistar rats, were submitted to middle cerebral artery occlusion (MCAO) and after 7 days sepsis to cecal ligation and perforation (CLP). Infarct size, neuroinflammation, oxidative stress, and mitochondrial activity were quantified 24 h after CLP in the prefrontal cortex and hippocampus. Survival and neurological score were assessed up to 15 days after MCAO or 8 days after CLP (starting at 2 h after MCAO) and memory at the end. KEY FINDINGS: CLP decreased survival, increased neurological impairments in MCAO females. Early, in male sepsis following MCAO led to increased glial activation in the brain structures, and increased TNF-α and IL-1ß in the hippocampus. All groups had higher IL-6 in both tissues, but the hippocampus had lower IL-10. CLP potentiated myeloperoxidase (MPO) in the prefrontal cortex of MCAO male and female. In MCAO+CLP, only male increased MPO and nitrite/nitrate in hippocampus. Males in all groups had protein oxidation in the prefrontal cortex, but only MCAO+CLP in the hippocampus. Catalase decreased in the prefrontal cortex and hippocampus of all males and females, and MCAO+CLP only increased this activity in males. Female MCAO+CLP had higher prefrontal cortex complex activity than males. In MCAO+CLP-induced long-term memory impairment only in females. SIGNIFICANCE: The parameters evaluated for early sepsis after ischemic stroke show a worse outcome for males, while females are affected during long-term follow-up.

Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor.

BACKGROUND: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition. OBJECTIVE: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis. METHODS: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days. RESULTS: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified. CONCLUSION: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.

Short-term hyperoxia induced mitochondrial respiratory chain complexes dysfunction and oxidative stress in lung of rats.

BACKGROUND: Oxygen therapy is an alternative for many patients with hypoxemia. However, this practice can be dangerous as oxygen is closely associated with the development of oxidative stress. METHODS: Male Wistar rats were exposed to hyperoxia with a 40% fraction of inspired oxygen (FIO2) and hyperoxia (FIO2 = 60%) for 120 min. Blood and lung tissue samples were collected for gas, oxidative stress, and inflammatory analyses. RESULTS: Hyperoxia (FIO2 = 60%) increased PaCO2 and PaO2, decreased blood pH and caused thrombocytopenia and lymphocytosis. In lung tissue, neutrophil infiltration, nitric oxide concentration, carbonyl protein formation and the activity of complexes I and II of the mitochondrial respiratory chain increased. FIO2 = 60% decreased SOD activity and caused several histologic changes. CONCLUSION: In conclusion, we have experimentally demonstrated that short-term exposure to high FIO2 can cause oxidative stress in the lung.

Cannabidiol effect on long-term brain alterations in septic rats: Involvement of PPARγ activation.

Sepsis is a life-threatening condition induced by a deregulated host response to infection. Post-sepsis injury includes long-term cognitive impairment, whose neurobiological mechanisms and effective treatment remain unknown. The present study was designed to determine the potential effects of cannabidiol (CBD) in a sepsis-associated encephalopathy (SAE) model and explore if peroxisome proliferator activated receptor gamma (PPARγ) is the putative mechanism underpinning the beneficial effects. SAE was induced in Wistar rats by cecal ligation and puncture (CLP) or sham (control). CLP rats received vehicle, CBD (10 mg/kg), PPARγ inhibitor (GW9662 - 1 mg/kg), or GW9662 (1 mg/kg) + CBD (10 mg/kg) intraperitoneally for ten days. During this period, the survival rate was recorded, and at the end of 10 days, a memory test was performed, and the prefrontal cortex and hippocampus were removed to verify brain-derived neurotrophic factor (BDNF), cytokines (IL-1ß, IL-6 and IL-10), myeloperoxidase activity, nitrite nitrate concentration, and lipid and protein carbonylation and catalase activity. Septic rats presented cognitive decline and an increase in mortality following CLP. Only CBD alone improved the cognitive impairment, which was accompanied by restoration of BDNF, reduced neuroinflammation, and oxidative stress, mainly in the hippocampus. This study shows that CLP induces an increase in brain damage and CBD has neuroprotective effects on memory impairment and neurotrophins, as well as against neuroinflammation and oxidative stress, and is mediated by PPARγ activation.

NLRP3 inflammasome activation increases brain oxidative stress after transient global cerebral ischemia in rats.

Pupurpose of the study: Oxidative stress has been reported to be an important mechanism for brain damage following ischemic stroke. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes has been demonstrated to perpetuate oxidative stress. Herein, we report the effect of NLRP3 inhibition with MCC950 on brain oxidative stress in an animal model of transient global cerebral ischemia.Materials and methods: Male Wistar rats received an intracerebroventricularly (icv) injection of MCC950 (140 ng/kg) or saline and were subjected to sham procedure or ischemia/reperfusion (I/R). Twenty-four hours after I/R, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, lipid peroxidation, protein carbonyls formation, superoxide dismutase (SOD) and catalase (CAT) activity were determined in the prefrontal cortex, hippocampus, cortex, cerebellum and striatum. Results: After I/R, MPO activity increased in the prefrontal cortex, hippocampus, cortex and cerebellum and N/N concentration elevated in the prefrontal cortex, hippocampus and cortex, while MCC950 decreased this level except in hippocampus. After I/R, lipid peroxidation enhanced in the prefrontal cortex and cerebellum and increased the oxidative protein damage in both structures and hippocampus. MCC950 decreased lipid peroxidation in the prefrontal cortex and decreased protein oxidative damage in all brain structures except in the striatum. SOD activity decreased in the cortex after I/R and MCC950 reestablished these levels. CAT activity decreased in the prefrontal cortex, hippocampus and cerebellum after I/R and MCC950 reestablished these levels in the prefrontal cortex.Conclusion: Our data provide novel demonstration that inhibiting NLRP3 activation with MCC950 reduces brain oxidative damage after cerebral I/R in rats.

The Infected Lungs and Brain Interface in COVID-19: The Impact on Cognitive Function.

Many coronavirus disease 2019 (COVID-19)-recovered patients report signs and symptoms and are experiencing neurological, psychiatric, and cognitive problems. However, the exact prevalence and outcome of cognitive sequelae is unclear. Even though the severe acute respiratory syndrome coronavirus 2 has target brain cells through binding to angiotensin-converting enzyme 2 (ACE2) receptor in acute infection, several studies indicate the absence of the virus in the brain of many COVID-19 patients who developed neurological disorders. Thus, the COVID-19 mechanisms for stimulating cognitive dysfunction may include neuroinflammation, which is mediated by a sustained systemic inflammation, a disrupted brain barrier, and severe glial reactiveness, especially within the limbic system. This review explores the interplay of infected lungs and brain in COVID-19 and its impact on the cognitive function.

Sex differences on the response to antidepressants and psychobiotics following early life stress in rats.

Major depressive disorder (MDD) is the most prevalent mood disorder globally. Most antidepressants available for the treatment of MDD increase the concentration of monoamines in the synaptic cleft. However, such drugs have a high latency time to obtain benefits. Thus, new antidepressants with fast action and robust efficacy are very important. This study evaluated the effects of escitalopram, ketamine, and probiotic Bifidobacterium infantis in rats submitted to the maternal deprivation (MD). MD rats received saline, escitalopram, ketamine, or probiotic for 10, 30, or 50 days, depending on the postnatal day (PND):21, 41, and 61. Following behavior, this study examined the integrity of the blood-brain barrier (BBB) and oxidative stress markers. MD induced depressive-like behavior in females with PND21 and males with PND61. All treatments reversed depressive-like behavior in females and escitalopram and ketamine in males. MD induced an increase in the permeability of the BBB, an imbalance between oxidative stress and antioxidant defenses. Treatments regulated the oxidative damage and the integrity of the BBB induced by MD. The treatment with escitalopram, ketamine, or probiotics may prevent behavioral and neurochemical changes associated with MDD, depending on the developmental period and gender.

Hyperoxia by short-term promotes oxidative damage and mitochondrial dysfunction in rat brain.

Oxygen (O2) therapy is used as a therapeutic protocol to prevent or treat hypoxia. However, a high inspired fraction of O2 (FIO2) promotes hyperoxia, a harmful condition for the central nervous system (CNS). The present study evaluated parameters of oxidative stress and mitochondrial dysfunction in the brain of rats exposed to different FIO2. Male Wistar rats were exposed to hyperoxia (FIO2 40 % and 60 %) compared to the control group (FIO2 21 %) for 2 h. Oxidative stress, neutrophilic infiltration, and mitochondrial respiratory chain enzymes were determined in the hippocampus, striatum, cerebellum, cortex, and prefrontal cortex after O2 exposure. The animals exposed to hyperoxia showed increased lipid peroxidation, formation of carbonyl proteins, N/N concentration, and neutrophilic infiltration in some brain regions, like hippocampus, striatum, and cerebellum being the most affected. Furthermore, CAT activity and activity of mitochondrial enzyme complexes were also altered after exposure to hyperoxia. Rats exposed to hyperoxia showed increase in oxidative stress parameters and mitochondrial dysfunction in brain structures.

Diabetes Exacerbates Sepsis-Induced Neuroinflammation and Brain Mitochondrial Dysfunction.

Sepsis is a life-threatening organ dysfunction, which demands notable attention for its treatment, especially in view of the involvement of immunodepressed patients, as the case of patients with diabetes mellitus (DM), who constitute a population susceptible to develop infections. Thus, considering this endocrine pathology as an implicatory role on the immune system, the aim of this study was to show the relationship between this disease and sepsis on neuroinflammatory and neurochemical parameters. Levels of IL-6, IL-10, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and mitochondrial respiratory chain complexes were evaluated in the hippocampus and prefrontal cortex 24 h after sepsis by cecal ligation and perforation (CLP) in Wistar rats induced to type 1 diabetes by alloxan (150 mg/kg). It was verified that diabetes implied immune function after 24 h of sepsis, since it contributed to the increase of the inflammatory process with higher production of IL-6 and decreased levels of IL-10 only in the hippocampus. In the same brain area, a several decrease in NGF level and activity of complexes I and II of the mitochondrial respiratory chain were observed. Thus, diabetes exacerbates neuroinflammation and results in mitochondrial impairment and downregulation of NGF level in the hippocampus after sepsis.

Effects of Ethanolic Extract of Cynara cardunculus (Artichoke) Leaves on Neuroinflammatory and Neurochemical Parameters in a Diet-Induced Mice Obesity Model.

This study aimed to evaluate the effect of Cynara cardunculus leaf ethanol extract on inflammatory and oxidative stress parameters in the hypothalamus, prefrontal cortex, hippocampus, striatum, cerebral cortex and liver of high-fat diet-induced obese mice. Food intake, body weight, visceral fat weight, and liver weight were also evaluated. Male Swiss mice were divided into control (low-fat purified diet) and obese (high-fat purified diet) groups. After 6 weeks, mice were divided into control + saline, control + C. cardunculus leaf ethanol extract, obese + saline, obese + C. cardunculus leaf ethanol extract. Cynara cardunculus leaf ethanol extract (1600 mg/kg/day) or saline was administered orally for 4 weeks. Brain structures (hypothalamus, hippocampus, prefrontal cortex, striatum and cerebral cortex) and liver were removed. Treatment with C. cardunculus leaf ethanol extract did not affect body weight but did reduce visceral fat. Obesity can cause inflammation and oxidative stress and increase the activity of antioxidant enzymes in brain structures. Treatment with ethanolic extract of C. cardunculus leaves partially reversed the changes in inflammatory damage parameters and oxidative damage parameters and attenuated changes in the antioxidant defense. The C. cardunculus leaf ethanol extract benefited from the brains of obese animals by partially reversing the changes caused by the consumption of a high-fat diet and the consequent obesity. These results corroborate those of studies indicating that the C. cardunculus leaf ethanol extract can contribute to the treatment of obesity.

Lung-Brain Crosstalk in Sepsis: Protective Effect of Prophylactic Physical Exercise Against Inflammation and Oxidative Stress in Rats.

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. The crosstalk occurs between the primary focus of infection and lung and other organ systems including the central nervous system via soluble and cellular inflammatory mediators and that this involves both the innate and adaptive immune systems. These interactions are reflected by genomic changes and abnormal rates of cellular apoptosis. The lungs and the brain are rapidly affected due to an inflammatory response and oxidative stress in sepsis. Physical exercise promotes positive responses in the inflammatory cascade and oxidative/antioxidant system. In this sense, we aimed at determining the possible protectant effects of a physical exercise program against inflammation and oxidative stress on the lungs and the brain of rats subjected to sepsis. Adult male Wistar rats were randomly assigned to the sham + sedentary (S), sham + trained (T), and cecal ligation and perforation (CLP) + S and CLP + T and subjected to a physical exercise program using a treadmill for 21 days. Forty-eight hours after the last training session, sepsis was induced by the CLP model. Twenty-four hours later, the animals were euthanized and the lungs, the hippocampus, and the prefrontal cortex were harvested to determine the levels of cytokines by enzyme-linked immunosorbent assay (ELISA) and nitrite and reactive oxygen species production, oxidative damage to proteins, and antioxidant enzymes by spectrophotometric method. Sepsis increased the lung and brain levels of TNF-α, IL-1ß, and IL-6, while diminished IL-10 levels, elevated nitrite levels and reactive oxygen species production, augmented the levels of protein carbonyls and diminished the sulfhydryl content, and decreased SOD activity and GSH levels. The exercise program diminished the levels of TNF-α, IL-1ß, IL-6, nitrite, and reactive oxygen species production, as well as the levels of protein carbonyls but augmented the sulfhydryl content, and elevated SOD activity. In conclusion, the exercise program protected the lungs and the brain of septic rats against inflammation and oxidative stress.

Oxidative stress in multiple organs after sepsis in elderly rats.

Aging is a dynamic process, in which morphological and physiological changes occur at all levels, making the body more vulnerable to acute events. Elderly people are at greater risk of sepsis developing than younger people. Sepsis is a set of serious manifestations throughout the body produced by an infection, leading to events that compromise cell homeostasis as oxidative stress and is associated with organ dysfunction. The aim of this study was to evaluate multi-organ oxidative stress in old rats in an animal model of polymicrobial sepsis. Adult (60d) and old (210d) male Wistar rats were submitted to sepsis by cecal ligation and perforation (CLP) and control group (sham) only by laparotomy. The experimental groups were divided into sham 60d, sham 210d, CLP 60d and CLP 210d. Twenty-four hours after CLP, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins, superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in the lung, kidney, liver, heart, spleen, quadriceps and diaphragm. Aging potentiated the increase in MPO activity in the after sepsis in the lung, liver and spleen. Lipid oxidative damage occurred in all structures analyzed in the CLP groups, while only in the lung, liver and diaphragm the lipid peroxidation was higher in the CLP 210d group compared to 60d. Regarding protein damage, this potentiation happened only in the lung. The SOD activity in the lung, kidney, spleen and diaphragm there was a significant decrease in the CLP 210d group compared to the sham 60d group while in the CAT only in the lung and kidney. The findings in this study indicate that increasing age potentiated oxidative damage in different organs after sepsis by intensifying the presence of neutrophils, which possibly increased the damage to lipids and proteins with reduced activity of SOD and CAT.

Combination of electroconvulsive stimulation with ketamine or escitalopram protects the brain against inflammation and oxidative stress induced by maternal deprivation and is critical for associated behaviors in male and female rats.

This study aimed at evaluating the treatment effects with ketamine, electroconvulsive stimulation (ECS), escitalopram, alone or in combination in adult rats of both sexes, subjected to the animal model of maternal deprivation (MD). All groups were subjected to the forced swimming test (FST), splash and open field tests. The prefrontal cortex (PFC), hippocampus and serum were collected to analyze oxidative stress and inflammatory parameters. MD induced depressive-like behavior in the FST test in males and reduced grooming time in male and female rats. The treatments alone or combined reversed depressive and anhedonic behavior in females. In males, all treatments increased grooming time, except for ECS + escitalopram + ketamine. MD increased lipid peroxidation and protein carbonylation, nitrite/nitrate concentration and myeloperoxidase activity in the PFC and hippocampus of males and females. However, the treatment's response was sex dependent. Catalase activity decreased in the PFC of males and the PFC and hippocampus of females, and most treatments were not able to reverse it. MD increased the inflammation biomarkers levels in the PFC and hippocampus of males and females, and most treatments were able to reverse this increase. In all groups, a reduction in the interleukin-10 levels in the PFC and hippocampus of female and male rats was observed. Our study shows different responses between the sexes in the patterns evaluated and reinforces the use of the gender variable as a biological factor in MDD related to early stress and in the response of the therapeutic strategies used.

Folic acid alleviates the blood brain barrier permeability and oxidative stress and prevents cognitive decline in sepsis-surviving rats.

Sepsis is a complication of an infection which imbalance the normal regulation of several organ systems, including the central nervous system (CNS). Evidence points towards inflammation and oxidative stress as major steps associated with brain dysfunction in sepsis. Thus, we investigated the folic acid (FA) effect as an important antioxidant compound on acute brain dysfunction in rats and long term cognitive impairment and survival. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with FA (10 mg/kg after CLP) or vehicle (veh). Animals were divided into sham + veh, sham + FA, CLP + veh and CLP + FA groups. Twenty-four hours after surgery, the hippocampus and prefrontal cortex were obtained and assayed for levels of blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. Survival was performed during 10 days after surgery and memory was evaluated. FA reduced BBB permeability, MPO activity in hippocampus and pre frontal cortex in 24 h and lipid peroxidation in hippocampus and improves the survival rate after sepsis. Long term cognitive improvement was verified with FA in septic rats compared with CLP + veh. Our data demonstrates that FA reduces the memory impairment in 10 days after sepsis and mortality in part by decreasing BBB permeability and oxidative stress parameters in the brain.

Sex differences on the behavior and oxidative stress after ketamine treatment in adult rats subjected to early life stress.

This study aimed to evaluate the effects of ketamine, on behavioral parameters, oxidative stress, and inflammation in the brain of male and female rats submitted to the animal model of maternal deprivation (MD). Wistar rats were deprived of maternal care in the first 10 days of life (three hours daily). As adults, male and female rats were divided: control + saline deprived + saline and deprived + ketamine (15 mg/kg). The behavior was evaluated through the open field and forced swimming tests. Then brain was removed for analysis of oxidative damage, the activity of superoxide dismutase (SOD), catalase (CAT), and myeloperoxidase (MPO) activity, and levels of interleukin-6 (IL-6). MD induced depressive behavior in males and ketamine reversed these changes. MD induced an increase in lipid peroxidation in males and females; ketamine reversed these effects in males. Protein carbonylation was increased in males and females, with ketamine decreasing such effects. The concentration of nitrite/nitrate increased in males and females, whereas ketamine decreased this in the PFC of males. SOD and CAT activities were decreased in male and female deprived groups and deprived groups treated with ketamine. MPO activity and IL-6 levels increased in males subjected to MD and ketamine reversed this effect. The results suggest that stressful events in early life can induce behavioral, neuroimmune changes, and oxidative stress, however, such effects depend on sex and brain area. Ketamine presents anti-inflammatory and antioxidant properties and could be considered an alternative for individuals who are resistant to classical treatments.

Stanniocalcin 1 Inhibits the Inflammatory Response in Microglia and Protects Against Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a serious consequence of sepsis, triggered by the host response against an infectious agent, that can lead to brain damage and cognitive impairment. Several mechanisms have been proposed in this bidirectional communication between the immune system and the brain after sepsis as neuroinflammation, oxidative stress, and mitochondrial dysfunction. Stanniocalcin-1 (STC-1), an endogen neuroprotective protein, acts as an anti-inflammatory and suppresses superoxide generation through induction of uncoupling proteins (UCPs) in the mitochondria. Here, we demonstrated a protective role of STC-1 on inflammatory responses in vitro, in activated microglia stimulated with LPS, and on neuroinflammation, oxidative stress, and mitochondrial function in the hippocampus of rats subjected to an animal model of sepsis by cecal ligation and puncture (CLP), as well the consequences on long-term memory. Recombinant human STC-1 (rhSTC1) suppressed the pro-inflammatory cytokine production in LPS-stimulated microglia without changing the UCP-2 expression. Besides, rhSTC1 injected into the cisterna magna decreased acute hippocampal inflammation and oxidative stress and increased the activity of complex I and II activity of mitochondrial respiratory chain and creatine kinase at 24 h after sepsis. rhSTC1 was effective in preventing long-term cognitive impairment after CLP. In conclusion, rhSTC1 confers significant neuroprotection by inhibiting the inflammatory response in microglia and protecting against sepsis-associated encephalopathy in rats.

NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats.

Sepsis survivors present acute and long-term cognitive impairment and the pathophysiology of neurological dysfunction in sepsis involves microglial activation. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes have been demonstrated to perpetuate neuroinflammation. Thus, we investigated the involvement of the NLRP3 inflammasome activation on early and late brain changes in experimental sepsis. Two-month-old male Wistar rats were submitted to the sepsis model by cecal ligation and perforation (CLP group) or laparotomy only (sham group). Immediately after surgery, the animals received saline or NLRP3 inflammasome formation inhibitor (MCC950, 140 ng/kg) intracerebroventricularly. Prefrontal cortex and hippocampus were isolated for cytokine analysis, microglial and astrocyte activation, oxidative stress measurements, nitric oxide formation, and mitochondrial respiratory chain activity at 24 h after CLP. A subset of animals was followed for 10 days for survival assessment, and then behavioral tests were performed. The administration of MCC950 restored the elevation of IL-1ß, TNF-α, IL-6, and IL-10 cytokine levels in the hippocampus. NLRP3 receptor levels increased in the prefrontal cortex and hippocampus at 24 h after sepsis, associated with microglial, but not astrocyte, activation. MCC950 reduced oxidative damage to lipids and proteins as well as preserved the activity of the enzyme SOD in the hippocampus. Mitochondrial respiratory chain activity presented variations in both structures studied. MCC950 reduced microglial activation, decreased acute neurochemical and behavioral alteration, and increased survival after experimental sepsis.

Aging influences in the blood-brain barrier permeability and cerebral oxidative stress in sepsis.

Sepsis is a set of serious manifestations throughout the body produced by an infection, leading to changes that compromise cellular homeostasis and can result in dysfunction of the central nervous system. The elderly have a higher risk of developing sepsis than younger peoples. Under the influence of inflammatory mediators and oxidizing agents released in the periphery as a result of the infectious stimulus, changes occur in the blood-brain barrier (BBB) permeability, with neutrophil infiltration, the passage of toxic compounds, activation of microglia and production of reactive species that results in potentiation of neuroimmune response, with the progression of neuronal damage and neuroinflammation. The objective of this study is to compare BBB permeability and the development of oxidative stress in the hippocampus and prefrontal cortex of young and old rats submitted to polymicrobial sepsis induction. Male Wistar rats grouped into sham (60d), sham (210d), cecal ligation and perforation (CLP) (60d) and CLP (210d) with n = 16 per experimental group were evaluated using the CLP technique to induce sepsis. The brain regions were collected at 24 h after sepsis induction to determine BBB permeability, myeloperoxidase (MPO) activity as marker of neutrophil activation, nitrite/nitrate (N/N) levels as marker of reactive nitrogen species, thiobarbituric acid reactive substances as marker of lipid peroxidation, protein carbonylation as marker of protein oxidation, and activity of antioxidant enzyme catalase (CAT). There was an increase in the BBB permeability in the CLP groups, and this was enhanced with aging in both brain region. MPO activity in the brain regions increased in the CLP groups, along with a hippocampal increase in the CLP 210d group compared to the 60d group. The concentration of N/N in the brain region was increased in the CLP groups. The damage to lipids and proteins in the two structures was enhanced in the CLP groups, while only lipid peroxidation was higher in the prefrontal cortex of the CLP 210d group compared to the 60d. CAT activity in the hippocampus was decreased in both CLP groups, and this was also influenced by age, whereas in the prefrontal cortex there was only a decrease in CAT in the CLP 60d group compared to the sham 60d. These findings indicate that aging potentiated BBB permeability in sepsis, which possibly triggered an increase in neutrophil infiltration and, consequently, an increase in oxidative stress.

Lipoic Acid and Fish Oil Combination Potentiates Neuroinflammation and Oxidative Stress Regulation and Prevents Cognitive Decline of Rats After Sepsis.

Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1ß in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.