Acute effects of intracerebroventricular administration of α-ketoisocaproic acid in young rats on inflammatory parameters.

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inborn error of metabolism (IEM), responsible for the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, in addition to their α-keto acids α-ketoisocaproic acid (KIC), α-keto-ß-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) in the plasma and urine of patients. This process occurs due to a partial or total blockage of the dehydrogenase enzyme activity of branched-chain α-keto acids. Oxidative stress and inflammation are conditions commonly observed on IEM, and the inflammatory response may play an essential role in the pathophysiology of MSUD. We aimed to investigate the acute effect of intracerebroventricular (ICV) administration of KIC on inflammatory parameters in young Wistar rats. For this, sixteen 30-day-old male Wistar rats receive ICV microinjection with 8 µmol KIC. Sixty minutes later, the animals were euthanized, and the cerebral cortex, hippocampus, and striatum structures were collected to assess the levels of pro-inflammatory cytokines (INF-γ; TNF-α, IL-1ß). The acute ICV administration of KIC increased INF-γ levels in the cerebral cortex and reduced the levels of INF-γ and TNF-α in the hippocampus. There was no difference in IL-1ß levels. KIC was related to changes in the levels of pro-inflammatory cytokines in the brain of rats. However, the inflammatory mechanisms involved in MSUD are poorly understood. Thus, studies that aim to unravel the neuroinflammation in this pathology are essential to understand the pathophysiology of this IEM.

A crosstalk between gut and brain in sepsis-induced cognitive decline.

BACKGROUND: Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota-gut-brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors. METHODS: To test our hypothesis, adult Wistar rats were subjected to cecal-ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [11C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after CLP and non-CLP surgeries. At 24 h and 10 days after surgery, we evaluated the gut microbiome, bacterial metabolites, cytokines, microglia, and astrocyte markers. Ten days after sepsis induction, the animals were subjected to the novel object recognition (NOR) and the Morris water maze (MWM) test to assess their learning and memory. RESULTS: Compared to the control group, the 24-h and 10-day CLP groups showed increased [11C]PBR28 uptake, glial cells count, and cytokine levels in the brain. Results show that sepsis modulates the gut villus length and crypt depth, alpha and beta microbial diversities, and fecal short-chain fatty acids (SCFAs). In addition, sepsis surviving animals showed a significant cognitive decline compared with the control group. CONCLUSIONS: Since several pharmacological studies have failed to prevent cognitive impairment in sepsis survivors, a better understanding of the function of glial cells and gut microbiota can provide new avenues for treating sepsis patients.

Postmortem Evidence of Brain Inflammatory Markers and Injury in Septic Patients: A Systematic Review.

OBJECTIVES: Sepsis is a life-threatening organ dysfunction caused by a host's unregulated immune response to eliminate the infection. After hospitalization, sepsis survivors often suffer from long-term impairments in memory, attention, verbal fluency, and executive functioning. To understand the effects of sepsis and the exacerbated peripheral inflammatory response in the brain, we asked the question: What are the findings and inflammatory markers in the brains of deceased sepsis patients? To answer this question, we conducted this systematic review by the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: Relevant studies were identified by searching the PubMed/National Library of Medicine, PsycINFO, EMBASE, Bibliographical Index in Spanish in Health Sciences, Latin American and Caribbean Health Sciences Literature, and Web of Science databases for peer-reviewed journal articles published on April 05, 2021. STUDY SELECTION: A total of 3,745 articles were included in the primary screening; after omitting duplicate articles, animal models, and reviews, 2,896 articles were selected for the study. These studies were selected based on the title and abstract, and 2,772 articles were still omitted based on the exclusion criteria. DATA EXTRACTION: The complete texts of the remaining 124 articles were obtained and thoroughly evaluated for the final screening, and 104 articles were included. DATA SYNTHESIS: The postmortem brain had edema, abscess, hemorrhagic and ischemic injuries, infarction, hypoxia, atrophy, hypoplasia, neuronal loss, axonal injuries, demyelination, and necrosis. CONCLUSIONS: The mechanisms by which sepsis induces brain dysfunction are likely to include vascular and neuronal lesions, followed by the activation of glial cells and the presence of peripheral immune cells in the brain.

Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review.

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.

Coadministration of tianeptine alters behavioral parameters and levels of neurotrophins in a chronic model of Maple Syrup Urine disease.

Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.

Exposure to leucine induces oxidative stress in the brain of zebrafish.

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder caused by a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase complex leading to the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, and valine and their respective branched-chain α-ketoacids and corresponding hydroxy acids. Considering that Danio rerio, known as zebrafish, has been widely used as an experimental model in several research areas because it has favorable characteristics that complement other experimental models, this study aimed to evaluate oxidative stress parameters in zebrafish exposed to high levels of leucine (2 mM and 5 mM), in a model similar of MSUD. Twenty-four hours after exposure, the animals were euthanized, and the brain content dissected for analysis of oxidative stress parameters: thiobarbituric acid reactive substances (TBARS), 2',7'-dichlorofluorescein oxidation assay (DCF); content of sulfhydryl, and superoxide dismutase (SOD) and catalase (CAT) activities. Animals exposed to 2 mM and 5 mM leucine showed an increase in the measurement of TBARS and decreased sulfhydryl content. There were no significant changes in DCF oxidation. In addition, animals exposed to 2 mM and 5 mM leucine were found to have decreased SOD activity and increased CAT activity. Based on these results, exposure of zebrafish to high doses of leucine can act as a promising animal model for MSUD, providing a better understanding of the toxicity profile of leucine exposure and its use in future investigations and strategies related to the pathophysiology of MSUD.

The impact of the microbiota-gut-brain axis on Alzheimer's disease pathophysiology.

The gut microbiota is a complex ecosystem that comprises of more than 100 trillion symbiotic microbial cells. The microbiota, the gut, and the brain form an association, 'the microbiota-gut-brain axis,' and synchronize the gut with the central nervous system and modify the behavior and brain immune homeostasis. The bidirectional communication between gut and brain occurs via the immune system, the vagus nerve, the enteric nervous system, and microbial metabolites, including short-chain fatty acids (SCFAs), proteins, and tryptophan metabolites. Recent studies have implicated the gut microbiota in many neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we present an overview of gut microbiota, including Firmicutes, Bacteroidetes, SCFA, tryptophan, bacterial composition, besides age-related changes in gut microbiota composition, the microbiota-gut-brain axis pathways, the role of gut metabolites in amyloid-beta clearance, and gut microbiota modulation from experimental and clinical AD models. Understanding the role of the microbiota may provide new targets for treatment to delay the onset, progression, or reverse AD, and may help in reducing the prevalence of AD.

Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study.

BACKGROUND: Bacterial meningitis is a devastating central nervous system (CNS) infection with acute and long-term neurological consequences, including cognitive impairment. The aim of this study was to understand the association between activated microglia-induced neuroinflammation and post-meningitis cognitive impairment. METHOD: Meningitis was induced in male Wistar rats by injecting Streptococcus pneumoniae into the brain through the cisterna magna, and rats were then treated with ceftriaxone. Twenty-four hours and 10 days after meningitis induction, rats were imaged with positron emission tomography (PET) using [11C]PBR28, a specific translocator protein (TSPO) radiotracer, to determine in vivo microglial activation. Following imaging, the expression of TSPO, cardiolipin, and cytochrome c, inflammatory mediators, oxidative stress markers, and glial activation markers were evaluated in the prefrontal cortex and hippocampus. Ten days after meningitis induction, animals were subjected to behavioral tests, such as the open-field, step-down inhibitory avoidance, and novel object recognition tests. RESULTS: Both 24-h (acute) and 10-day (long-term) groups of rats demonstrated increased [11C]PBR28 uptake and microglial activation in the whole brain compared to levels in the control group. Although free from infection, 10-day group rats exhibited increased expression levels of cytokines and markers of oxidative stress, microglial activation (IBA-1), and astrocyte activation (GFAP) similar to those seen in the 24-h group. Acute meningitis induction also elevated TSPO, cytochrome c, and caspase-3 levels with no change in caspase-9 levels. Furthermore, upregulated levels of TSPO, cytochrome c, and caspase-3 and caspase-9 were observed in the rat hippocampus 10 days after meningitis induction with a simultaneous reduction in cardiolipin levels. Animals showed a cognitive decline in all tasks compared with the control group, and this impairment may be at least partially mediated by activating a glia-mediated immune response and upregulating TSPO. CONCLUSIONS: TSPO-PET could potentially be used as an imaging biomarker for microglial activation and long-term cognitive impairment post-meningitis. Additionally, this study opens a new avenue for the potential use of TSPO ligands after infection-induced neurological sequelae.

Prevention of Memory Impairment and Neurotrophic Factors Increased by Lithium in Wistar Rats Submitted to Pneumococcal Meningitis Model.

The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg) or tamoxifen (1 mg/kg) as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis.

Depression-Like Adult Behaviors may be a Long-Term Result of Experimental Pneumococcal Meningitis in Wistar Rats Infants.

Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS) with a high mortality rate. In addition to causing severe neurological sequelae infectious diseases of the CNS can play a significant role in the pathogenesis of neuropsychiatric disorders. In this study infant Wistar rats, postnatal day 11, received intracerebroventricular (i.c.v.) either artificial cerebrospinal fluid (CSF) or a Streptococcus pneumoniae suspension to a concentration of 1 × 106 colony-forming units (CFU). 18 h later animals received antibiotic treatment as usual during 7 days. On postnatal day 46, the animals received imipramine intraperitoneal (i.p.) or sterile NaCl during 14 days (postnatal days 46-60). Then, on postnatal days 59-60 we evaluated the consumption of sweet food (an index of anhedonia). On postnatal day 60 the animals were submitted to the forced swimming task. 60 min after this task the animals were decapitated and the blood was collected to evaluate adrenocorticotropic hormone (ACTH) and corticosterone. Immediately after blood collection the hippocampus was removed to evaluate brain-derived neurotropic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The meningitis group exhibited depressive-like behavior as evidenced by decreased sucrose intake and increased immobility time in the forced swimming task, and BDNF and GDNF decrease in the hippocampus. ACTH levels were increased in the blood. Imipramine treatment reversed depressive-like behaviors, re-established hippocampal BDNF and GDNF expression, and normalized ACTH levels in the blood. Here we demonstrate that meningitis during early life period can trigger depressive-like behavior in adult life of rats.

Folic acid prevented cognitive impairment in experimental pneumococcal meningitis.

Streptococcus pneumoniae is a common cause of bacterial meningitis, with a high mortality rate and neurological sequelae. In contrast, folic acid plays an important role in neuroplasticity and the preservation of neuronal integrity. In the present study, we evaluated the influence of folic acid on memory, oxidative damage, enzymatic defence, and brain-derived neurotrophic factor (BDNF) expression in experimental pneumococcal meningitis. In animals that received folic acid at a dose of 10 or 50 mg, there was a reduction in both crossing and rearing during an open-field task compared with the training session, demonstrating habituation memory. During a step-down inhibitory avoidance task, there was a difference between the training and the test sessions, demonstrating aversive memory. In the hippocampus, BDNF expression decreased in the meningitis group; however, adjuvant treatment with 10 mg of folic acid increased BDNF expression, decreased lipid peroxidation, protein carbonylation, nitrate/nitrite levels, and myeloperoxidase activity and increased superoxide dismutase activity. In frontal cortex adjuvant treatment with 10 mg of folic acid decreased lipid peroxidation and protein carbonylation. There is substantial interest in the role of folic acid and related pathways in nervous system function and in folic acid's potential therapeutic effects. Here, adjuvant treatment with vitamin B9 prevented memory impairment in experimental pneumococcal meningitis.

NLRP3 Activation Contributes to Memory Impairment in an Experimental Model of Pneumococcal Meningitis.

Bacterial meningitis is considered a life-threatening condition with high mortality rates. In response to the infection, signaling cascades, producing pro-inflammatory mediators trigger an exacerbated host immune response. Another inflammatory pathway occurs through the activation of inflammasomes. Studies highlight the role of the NLR family pyrin domain containing 3 (NLRP3) in central nervous system disorders commonly involved in neuroinflammation. We aimed to investigate the role of NLRP3 and its inhibitor MCC950 on neurochemical, immunological, and behavioral parameters in the early and late stages of experimental pneumococcal meningitis. For this, adult male Wistar rats received an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a placebo. The animals were divided into control/saline, control/MCC950, meningitis/saline, and meningitis/MCC950. Immediately after the meningitis induction, the animals received 140 ng/kg MCC950 via intracisternal injection. For the acute protocol, 24 h after induction, brain structures were collected to evaluate cytokines, NLRP3, and microglia. In the long-term group, the animals were submitted to open field and recognition of new objects tests at ten days after the meningitis induction. After the behavioral tests, the same markers were evaluated. The animals in the meningitis group at 24 h showed increased levels of cytokines, NLRP3, and IBA-1 expression, and the use of the MCC950 significantly reduced those levels. Although free from infection, ten days after meningitis induction, the animals in the meningitis group had elevated cytokine levels and demonstrated behavioral deficits; however, the single dose of NLRP3 inhibitor rescued the behavior deficits and decreased the brain inflammatory profile.

Attenuation of cognitive impairment by the nonbacteriolytic antibiotic daptomycin in Wistar rats submitted to pneumococcal meningitis.

BACKGROUND: Streptococcus pneumoniae is associated with neurologic sequels, such as, seizures, sensory-motor deficits, hearing loss, learning and memory impairment, which can occur in approximately 30 to 52% of surviving patients. Neuronal damage can be caused by intense inflammatory reaction and direct effects of the bacteria virulence factors. The aim of the present study was to evaluate the effects of the nonbacteriolytic antibiotic daptomycin versus ceftriaxone on behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. RESULTS: Ten days after induction we verified that the meningitis group with daptomycin treatment showed retention of aversive memory; it presented memory of the object recognition at short term and long term. In continuous multiple-trials step-down inhibitory avoidance task the meningitis group with ceftriaxone treatment required approximately two times more stimulus to reach the acquisition criterion when compared with meningitis group with daptomycin treatment. However, in the habituation memory test there were no differences in the number of crossings and rearings in training and task sessions demonstrating habituation impairment to the environment task in both meningitis groups. CONCLUSIONS: The evidence of the present study shows the potential alternative of the treatment with daptomycin in preventing learning and memory impairments caused by pneumococcal meningitis. Further investigations are necessary to provide support for evaluation of daptomycin as an alternative treatment of bacterial meningitis.

Evaluation of energetic metabolism in the rat brain after meningitis induction by Klebsiella pneumoniae.

BACKGROUND: Bacterial meningitis is an infection of the central nervous system characterised by strong inflammatory response. The brain is highly dependent on ATP, and the cell energy is obtained through oxidative phosphorylation, a process which requires the action of various respiratory enzyme complexes and creatine kinase (CK) as an effective buffering system of cellular ATP levels in tissues that consume high energy. OBJECTIVES: Evaluate the activities of mitochondrial respiratory chain complexes I, II, III, IV and CK activity in hippocampus and cortex of the Wistar rat submitted to meningitis by Klebsiella pneumoniae. METHODS: Adult Wistar rats received either 10 µl of sterile saline as a placebo or an equivalent volume of K. pneumoniae suspension. The animals were killed in different times at 6, 12, 24 and 48 h after meningitis induction. Another group was treated with antibiotic, starting at 16 h and continuing daily until their decapitation at 24 and 48 h after induction. RESULTS: In the hippocampus, the meningitis group without antibiotic treatment, the complex I was increased at 24 and 48 h, complex II was increased at 48 h, complex III was inhibited at 6, 12, 24 and 48 h and in complex IV all groups with or without antibiotic treatment were inhibited after meningitis induction, in the cortex there was no alteration. Discussion Although descriptive, our results show that antibiotic prevented in part the changes of the mitochondrial respiratory chain. The meningitis model could be a good research tool to study the biological mechanisms involved in the pathophysiology of the K. pneumoniae meningitis.

Imipramine reverses depressive-like parameters in pneumococcal meningitis survivor rats.

Pneumococcal meningitis is a severe infectious disease of the central nervous system, associated with acute inflammation and might cause damage to the host, such as deafness, blindness, seizure, and learning deficits. However, infectious diseases can play a significant role in the etiology of neuropsychiatric disturbances. In this context, we evaluated depressive-like parameters; corticosterone and ACTH levels in pneumococcal meningitis surviving rats. Wistar rats underwent a magna cistern tap receiving either 10 µL sterile saline or a Streptococcus pneumoniae suspension at the concentration of 5 × 10(9) cfu/mL. After 3 days of meningitis induction procedure, the animals were treated with imipramine at 10 mg/kg or saline for 14 days (3rd-17th day). The consumption of sweet food was measured for 7 days (10th-17th day). The meningitis group decreased the sucrose intake and increased the levels of corticosterone and ACTH levels in the serum and TNF-α in the cortex; however, the treatment with imipramine reverted the reduction of sweet food consumption, normalized hormonal levels and TNF-α in the cortex. Our results supported the hypothesis that the pneumococcal meningitis surviving rats showed depressive-like behavior and alterations in the hypothalamus-pituitary-adrenal axis.

Acetylcholinesterase activity in the rat brain after pneumococcal meningitis.

Pneumococcal meningitis is a life-threatening disease characterized by acute purulent infection of the meninges causing neuronal injury, cortical necrosis and hippocampal apoptosis. Cholinergic neurons and their projections are extensively distributed throughout the central nervous system. The aim of this study was to assess acetylcholinesterase activity in the rat brain after pneumococcal meningitis. In the hippocampus, frontal cortex and cerebrospinal fluid, acetylcholinesterase activity was found to be increased at 6, 12, 24, 48 and 96 hr without antibiotic treatment, and at 48 and 96 hr with antibiotic treatment. Our data suggest that acetylcholinesterase activity could be related to neuronal damage induced by pneumococcal meningitis.

Antioxidant treatment prevents cognitive impairment and oxidative damage in pneumococcal meningitis survivor rats.

Pneumococcal meningitis is associated with the highest fatality case ratios in the world. Most of patients that survive present neurologic sequelae at later times as well as biochemicals alterations such as oxidative stress in both earlier and later times after central nervous system infection. In this context, we evaluated the effect of antioxidant treatment on memory and oxidative parameters in the hippocampus of meningitis survivor rats 10 days after infection. To this aim, the animals underwent a magna cistern tap receiving either 10 µL sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension at the concentration 5x10(9) cfu/mL. The animals submitted to meningitis were divided into the following groups: 1) treated with antibiotic, 2) treated with basic support plus N-acetylcysteine, 3) treated with basic support plus deferoxamine, 4) treated with basic support plus N-acetylcysteine and deferoxamine, or 5) treated with N-acetylcysteine plus deferoxamine. Ten days after meningitis, the animals underwent inhibitory avoidance and habituation to an open field tasks and, immediately after, were assessed for oxidative damage in the hippocampus and cortex. The meningitis group showed significantly decreased performance in latency retention compared with the sham group in the inhibitory avoidance task. In the open-field task, the meningitis group presented memory impairment after meningitis. All these memory impairments were prevented by N-acetylcysteine plus deferoxamine with or without basic support and its isolate use. In addition, there was an increase of lipid phosphorylation in cortex and hippocampus and all the combined antioxidants attenuated lipid phosphorylation in both structures. On the other hand, there was an increase of protein phosphorylation in cortex and N-acetylcysteine plus deferoxamine with or without basic support prevented it. Thus, we hypothesize that oxidative stress may be related to cognitive impairment in pneumococcal meningitis.

Dysfunctional Glymphatic System with Disrupted Aquaporin 4 Expression Pattern on Astrocytes Causes Bacterial Product Accumulation in the CSF during Pneumococcal Meningitis.

Pneumococcal meningitis, inflammation of the meninges due to an infection of the Central Nervous System caused by Streptococcus pneumoniae (the pneumococcus), is the most common form of community-acquired bacterial meningitis globally. Aquaporin 4 (AQP4) water channels on astrocytic end feet regulate the solute transport of the glymphatic system, facilitating the exchange of compounds between the brain parenchyma and the cerebrospinal fluid (CSF), which is important for the clearance of waste away from the brain. Wistar rats, subjected to either pneumococcal meningitis or artificial CSF (sham control), received Evans blue-albumin (EBA) intracisternally. Overall, the meningitis group presented a significant impairment of the glymphatic system by retaining the EBA in the CSF compartments compared to the uninfected sham group. Our results clearly showed that during pneumococcal meningitis, the glymphatic system does not function because of a detachment of the astrocytic end feet from the blood-brain barrier (BBB) vascular endothelium, which leads to misplacement of AQP4 with the consequent loss of the AQP4 water channel's functionality. IMPORTANCE The lack of solute drainage due to a dysfunctional glymphatic system leads to an increase of the neurotoxic bacterial material in the CSF compartments of the brain, ultimately leading to brain-wide neuroinflammation and neuronal damage with consequent impairment of neurological functions. The loss of function of the glymphatic system can therefore be a leading cause of the neurological sequelae developing post-bacterial meningitis.

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.

Oxidative stress, cytokine/chemokine and disruption of blood-brain barrier in neonate rats after meningitis by Streptococcus agalactiae.

We verify the levels of cytokine/chemokine, myeloperoxidase activity, oxidative stress and disruption of BBB in hippocampus and cortex of the neonate Wistar rats after meningitis by S. agalactiae. In the hippocampus the levels were increased of CINC-1 at 6 h and 12 h, IL-1ß at 6, 12 and 24 h, IL-6 at 6, 24 and 96 h, IL-10 at 24, 48 and 96 h and TNF-α at 24 h and 96 h. In the cortex the CINC-1 and IL-1ß levels were found increased at 6 h. The MPO activity was significantly elevated at 24, 48 and 98 h in hippocampus and at 6, 12, 24, 48 and 96 h in the cortex. The breakdown of BBB started at 12 h.TBARS levels were elevated in the hippocampus at 6, 12, 24, 48, 72 and 96 h and cortex at 72 and 96 h. Protein carbonyls were elevated in the hippocampus and cortex at 6, 24, 48, 72 and 96 h. There was a decrease of SOD activity in hippocampus and in cortex. Catalase activity was elevated in hippocampus at 6 h and in the cortex at 12 and 96 h. Neonatal bacterial infections of the CNS are severe, the interference with the complex network of cytokines/chemokine, other inflammatory mediators and oxidants tend to aggravate the illness and can be involved in the breakdown of the BBB.