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.

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.

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.

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.

Gold nanoparticles potentiates N-acetylcysteine effects on neurochemicals alterations in rats after polymicrobial sepsis.

Herein, we report the effect of gold nanoparticles (AuNP) and n-acetylcysteine (NAC) isolated or in association as important anti-inflammatory and antioxidant compounds on brain dysfunction in septic rats. Male Wistar rats after sham operation or caecal ligation and perforation (CLP) were treated with subcutaneously injection of AuNP (50 mg/kg) and/or NAC (20 mg/kg) or saline immediately and 12 h after surgery. Twenty-four hours after CLP, hippocampus and prefrontal cortex were obtained and assayed for myeloperoxidase (MPO) activity, cytokines, lipid peroxidation, protein carbonyls formation, mitochondrial respiratory chain, and CK activity. AuNP + NAC association decreased MPO activity and pro-inflammatory cytokines production, being more effective than NAC or AuNP isolated treatment. AuNP + NAC association and NAC isolated treatment decreased oxidative stress to lipids in both brain structures, while protein oxidation decreased only in the hippocampus of AuNP + NAC association-treated animals. Complex I activity was increased with AuNP + NAC association and NAC isolated in the hippocampus. Regarding CK activity, AuNP and AuNP + NAC association increased this marker in both brain structures after CLP. Our data provide the first experimental demonstration that AuNP and NAC association was able to reduce sepsis-induced brain dysfunction in rats by decreasing neuroinflammation, oxidative stress parameters, mitochondrial dysfunction and CK activity.

Oxidative stress in the choroid plexus contributes to blood-cerebrospinal fluid barrier disruption during sepsis development.

BACKGROUND: The choroid plexus (CP), main component of blood-cerebrospinal fluid barrier (BCSFB), protects the brain from peripheral inflammation similar to the blood-brain barrier. Thus, CP is considered a critical target site of oxidative damage, which in sepsis oxidative stress is likely to be a major step in the development of brain damage. Functional alterations in CP may be associated with sepsis-induced brain injury. However, there is no description on the mechanisms associated with BCSFB disruption during sepsis development. MATERIALS AND METHODS: To test this hypothesis, we examined time-dependent oxidative stress markers in CP and permeability of BCSFB in rats submitted to polymicrobial sepsis by cecal ligation and puncture (CLP) or sham surgery (control). We assessed albumin cerebrospinal fluid/plasma concentration quotient (Qalb), an index of BCSFB dysfunction and in CP samples, the oxidative damage in lipids, proteins, antioxidant enzymes and nitrite/nitrate (N/N) concentration in 12, 24 and 48 h after CLP. RESULTS: The increase of BCSFB permeability is time-related to the increase of N/N concentration, oxidative damage to lipid and proteins, and decrease of antioxidant enzyme superoxide dismutase activity at 12 h in the CP; and decrease of catalase activity in 12 and 24 h. CONCLUSIONS: In experimental sepsis the BCSFB dysfunction occurs and oxidative stress seems to be a major step in this dysfunction.