[Show abstract][Hide abstract] ABSTRACT: Pain is one of the main symptoms of multiple sclerosis, a demyelinating disease of the central nervous system that affects millions of people worldwide. The experimental autoimmune encephalomyelitis (EAE) is considered an experimental model of multiple sclerosis, and besides motor weakness, hypernociception is one of the clinical signs of animals with EAE. In this study, we investigated the influence of some cytokines in the generation of the hypernociceptive response in a mouse model of EAE using MOG35-55. We measured some cytokines in the dorsal root ganglia (DRG), an important anatomical structure involved in pain. We found increased levels of the cytokines TNF-α, IL-1β, and Kc in DRGs of animals with EAE. We used the antibody IL-1ra to antagonize the effects of IL-1β, and animals presented a decrease in the hypernociceptive response. Thus, our results suggest that hypernociception in this experimental model of EAE may be a consequence of the increase in some cytokines in DRGs, especially IL-1β.
Full-text · Article · Nov 2015 · Molecular Neurobiology
[Show abstract][Hide abstract] ABSTRACT: Objective:
To assess the frequency of overweight and obesity in children and adolescents with autism spectrum disorder (ASD) and with attention deficit/hyperactivity disorder (ADHD) and their parents, in comparison with children and adolescents without developmental disorders.
Anthropometric measures were obtained in 69 outpatients with ASD (8.4±4.2 years old), 23 with ADHD (8.5± 2.4) and 19 controls without developmental disorders (8.6±2.9) between August and November 2014. Parents of patients with ASD and ADHD also had their anthropometric parameters taken. Overweight was defined as a percentile ≥85; obesity as a percentile ≥ 95; and underweight as a percentile ≤5. For adults, overweight was defined as a BMI between 25 and 30kg/m2 and obesity as a BMI higher than 30kg/m2.
Children and adolescents with ASD and ADHD had higher BMI percentile (p<0.01) and z-score (p<0.01) than controls, and increased frequency of overweight and obesity (p=0.04). Patients with ASD and ADHD did not differ between them in these variables, nor regarding abdominal circumference. Parents of children with ASD and ADHD did not differ between themselves.
Children and adolescents with ASD and ADHD are at a higher risk of overweight and obesity than children without developmental problems in the community.
[Show abstract][Hide abstract] ABSTRACT: Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3+CD8+ T cells were significantly reduced in the brain of infected PI3Kγ-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.
[Show abstract][Hide abstract] ABSTRACT: Pneumococcal meningitis is associated with neurologic sequelae, such as, learning and memory impairment. Most currently a nonbacteriolytic antibiotic has been investigated to minimize inflammatory host response and prevented cognitive damage. In the present study, we compared daptomycin (DPTO) or ceftriaxone (CFX) treatment on inflammatory parameters and on blood-brain barrier (BBB) integrity in experimental pneumococcal meningitis. In the first step, the animals received an intracisternal (i.c.) injection of 10 µl of a S. pneumoniae suspension and were treated with CFX or DPTO at 18 h and were killed at 18, 20, 24, 36 and 40 h. In the hippocampus, tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), IL-10 and brain-derived neurotrophic factor (BDNF) levels were not different between both treatments, however, IL-4 and CINC-1 levels decreased in CFX group. In frontal cortex, TNF-α, IL-4, IL-6, IL-10 and BDNF levels were not different between both treatments. Only cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels decreased at 40 h with CFX treatment. In the second step the animals received DPTO or CFX during 7 days and were killed 10 days after induction. TNF-α, IL-6, IL-10, CINC-1 and BDNF levels were not different between both treatments in the hippocampus, however, IL-4 levels decreased in CFX treatment. In the third step: the animals received by i.c. 10 µl of a S. pneumoniae suspension or artificial CSF and were treated with CFX or DTPO with a single dose of antibiotic and BBB breakdown was assessed; however both antibiotics prevented the BBB disruption. Equally both treatments protected the BBB integrity and there were no significant difference in cytokines production.
No preview · Article · May 2014 · Current Neurovascular Research
[Show abstract][Hide abstract] ABSTRACT: Infection with Plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and
mortality. Plasmodium berghei Anka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular
receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice
infected with P. berghei Anka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature,
and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis
factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines
required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted
in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal
expression of SOCS3 in spleen and brain, and P. berghei Anka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest
that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is,
to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.
Full-text · Article · May 2014 · Infection and immunity
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: Evaluate the levels of a neurotrophic factor and some neurotrophins in the plasma of patients with Autism Spectrum Disorders (ASD). DESIGN: This study enrolled 30 children with ASD and 19 healthy children. Plasma levels of the neurotrophins BDNF, NGF, NT3, NT4 and of the neurotrophic factor GDNF were measured by Enzyme-Linked Immunosorbent Assay. SETTING: The etiopathogenesis of ASD is largely unknown, but it seems to involve dysfunction in several biological systems. One of these systems comprises the neurotrophic factors, which are molecules involved in many processes in the central nervous system, including neuronal survival, synaptogenesis and synaptic plasticity. Recent studies have shown association between neurotrophic factors and ASD. RESULTS: No differences in plasma BDNF, NGF, NT3, NT4 and GDNF were found between ASD and control. Neurotrophic factors are not altered in ASD. CONCLUSIONS: These molecules may play a minor role in ASD.
No preview · Article · Jan 2014 · Neuro endocrinology letters
[Show abstract][Hide abstract] ABSTRACT: Background and objective:
The etiopathogenesis of autism spectrum disorders (ASD) is largely unknown, but it seems to involve dysfunction in several biological systems. Among many possible biological pathways, the immune system has emerged as potentially involved. Recent studies have shown association between cytokines (molecules that mediate immune cell interaction) and ASD. Adipokines are cytokines secreted mainly by adipose tissue and may have systemic effects. The main objective of this study was to compare the plasma levels of three adipokines between patients with ASD and healthy controls. Another aim was to correlate the levels of these adipokines and the severity of autistic symptoms as measured by the Social Responsiveness Scale (SRS).
We collected plasma from 30 patients and 19 controls and measured the levels of adiponectin, leptin and resistin using a commercially available kit. We also used the SRS as a tool to assess the severity of autistic symptoms.
We found decreased levels of resistin, increased levels of leptin and unaltered levels of adiponectin in plasma from ASD subjects in comparison with controls. There was also a negative correlation between the levels of adiponectin and the severity of symptoms as assessed by the SRS.
There are significant changes in the plasma levels of adipokines from patients with ASDs. They suggest the occurrence of systemic changes in ASD and may be hallmarks of the disease.
Full-text · Article · Dec 2013 · Neuropsychobiology
[Show abstract][Hide abstract] ABSTRACT: Cerebral malaria (CM) is a clinical syndrome resulting from Plasmodium falciparum infection. A wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. CM pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. Artesunate has been accepted as the most effective drug for treating severe malaria. Besides its antiparasitic activity, an anti-inflammatory property has also been reported. In the current study, the immunomodulatory role of artesunate was investigated using a Plasmodium berghei ANKA model of CM, trough evaluation of behavioural changes and cytokines expression in hippocampus and in frontal cortex.
C57Bl/6 mice were infected with P. berghei by intraperitoneal route, using a standardized inoculation of 106 parasitized erythrocytes. Memory function was evaluated using the step-down inhibitory avoidance test. The mRNA expression of IFN-gamma, IL-1beta, IL-6 and TNF in the frontal cortex and hippocampus of control and infected mice on day 5 post-infection were estimated by quantitative real time PCR. Plasmodium berghei -infected mice also received intraperitoneally a single dose of artesunate (32 mg/kg) on day 4 post-infection, and 24 hours after treatment behavioural and immunological analysis were performed. The protein levels of cytokines IL-2, IL-6, IL-10, IL-17, IFN-gamma, TNF in the serum, frontal cortex and hippocampus of controls and P. berghei -infected mice treated or not treated with artesunate were determined using a cytometric bead array (CBA) kit. The survival and neurological symptoms of CM were also registered.
CM mice presented a significant impairment of aversive memory compared to controls on day 5 post-infection. A higher mRNA expression of pro-inflammatory cytokines was found in the hippocampus and frontal cortex of infected mice. A single dose of artesunate was also able to decrease the expression of inflammatory cytokines in the hippocampus and frontal cortex of P. berghei-infected mice. In parallel, a significant improvement in neurological symptoms and survival were observed in artesunate treated mice.
In summary, the current study provided further evidence that CM affects key brain areas related to cognition process. In addition, different patterns of cytokine expression during the course of CM could be modulated by a single administration of the anti-malarial artesunate.
[Show abstract][Hide abstract] ABSTRACT: Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice.
C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/lmperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-iβ was measured by ELISA.
Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-iβ were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre-treatment.
Our results suggest that the blockade of the CXCR1/2 receptors by reparixin promotes neuroprotective effects by reducing the levels of polymorphonuclear infiltration in the brain and the tissue damage associated with middle cerebral artery occlusion and reperfusion.
Full-text · Article · Mar 2013 · Clinics (São Paulo, Brazil)
[Show abstract][Hide abstract] ABSTRACT: Background
The neuroinflammatory response aimed at clearance of herpes simplex virus-1 (HSV-1) plays a key role in the pathogenesis of neuroaxonal damage in herpetic encephalitis. Leukocytes activated in an adaptive immune response access brain tissue by passing through the blood–brain barrier. The chemokine CCL5/RANTES is involved in recruitment of these cells to the brain acting via the receptors CCR1, CCR3 and mainly CCR5. Here, we evaluated the role of CCR5 on traffic of leukocytes in the brain microvasculature, cellular and cytokines profile in a severe form of herpetic encephalitis.
Wild type and mice lacking CCR5 (CCR5-/-) were inoculated intracerebrally with 104 PFU of neurotropic HSV-1. We evaluated the traffic of leukocytes in the brain microvasculature using intravital microscopy and the profile of cytokines by Enzyme-Linked Immunosorbent Assay at 1 day post infection. Flow cytometry and histopathological analyses were also carried out in brain tissue. Absence of CCR5 leads to lower viral load and an increased leukocyte adhesion in brain microvasculature, predominantly of neutrophils (CD11+ Ly6G+ cells). Moreover, there was a significant increase in the levels of MIP-1/CCL2, RANTES/CCL5, KC/CXCL1 and MIG/CXCL9 in the brain of infected CCR5-/- mice.
These results suggest that the absence of CCR5 may boost the immune response with a high neutrophil recruitment which most likely helps in viral clearance. Nonetheless, the elevated immune response may be detrimental to the host.
[Show abstract][Hide abstract] ABSTRACT: Sepsis can lead to long-term cognitive changes, including memory and learning deficits, which are known as septic encephalopathy (SE). SE also includes behavioral changes. The underlying mechanism of SE is unknown, and several mechanisms have been proposed. This study investigated late anxiety-like behavior, serum cytokine levels and brain cytokine production in C57BL/6 mice subjected to polymicrobial sepsis induced by sublethal cecum ligature and puncture (CLP). Anxiety-like behavior and locomotor activity were assessed in mice 10 days after sham operation or CLP procedure using the elevated plus maze, contextual fear conditioning, and open field test. Brain and serum concentrations of the cytokines TNF-α, IFN-γ, IL-1β, IL-6, and IL-10 were determined by ELISA. We found that mice subjected to polymicrobial sepsis presented anxiety-like behavior, which was accompanied by increased serum TNF-α and brain TNF-α, IFN-γ, IL-1β, and IL-6 levels, 10 days after the surgical procedure. These findings suggest an involvement of central nervous system inflammatory mediators in the anxiety-like symptoms found in SE.
Full-text · Article · Dec 2012 · Neurotoxicity Research
[Show abstract][Hide abstract] ABSTRACT: Dengue virus is a human pathogen that may cause meningoencephalitis and other neurological syndromes. The current study investigated anxiety-like behavior and expression of proinflammatory cytokines and pro-apoptotic caspase-3 in the hippocampus of C57BL/6 mice infected with non-adapted Dengue virus 3 genotype I (DENV-3) inoculated intracranially with 4×10(3) (plaque-forming unit) PFU. Anxiety-like behavior was assessed in control and DENV-3 infected mice using the elevated plus maze. The open field test was performed to evaluate locomotor activity. Histopathological changes in CA regions of the hippocampus were assessed by haematoxylin and eosin staining. Immunoreactive and protein levels of cleaved caspase-3 were also analyzed in the hippocampus. The mRNA expression of IL-6 and TNF-α in the hippocampus were estimated by quantitative real time (polymerase chain reaction) PCR. All procedures were conducted on day 5 post-infection. We found that DENV-3 infected mice presented higher levels of anxiety in comparison with controls (p≤0.05). No difference in motor activity was found between groups (p=0.77). The infection was followed by a significant increase of TNF-α and IL-6 mRNA expression in the hippocampus (p≤0.05). Histological analysis demonstrated meningoencephalitis with formation of perivascular cuffs, infiltration of immune cells and loss of neurons at CA regions of hippocampus. Numerous caspase-3 positive neurons were visualized at CA areas in DENV-3 infected mice. Marked increase of cleaved caspase-3 levels were observed after infection. This study described anxiety-like behavior, hippocampal inflammation and neuronal apoptosis associated with DENV-3 infection in the central nervous system.
Full-text · Article · Feb 2012 · Behavioural brain research
[Show abstract][Hide abstract] ABSTRACT: The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.
Preview · Article · Dec 2011 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis is a neuroinflammatory disease that results in serious neurological disability. Besides physical impairment, behavioral symptoms are also common in patients with multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is considered to be a model of multiple sclerosis and mimics the main features of the disease, such as demyelination and motor impairment. In this work, we aimed to study behavioral parameters in animals with EAE using the MOG(35-55) model in C57BL/6 mice. We analyzed memory and anxiety in animals using the elevated plus maze, the step down inhibitory avoidance task and the memory recognition test. No differences in any tests were found when comparing controls and animals induced with EAE. Therefore, we conclude that behavioral changes in animals with EAE induced with MOG(35-55) are probably subtle or absent.
Preview · Article · Dec 2011 · Arquivos de neuro-psiquiatria
[Show abstract][Hide abstract] ABSTRACT: Cerebral malaria is a severe form of the disease that may result, in part, from an overt inflammatory response during infection by Plasmodium falciparum. The understanding of the pathogenesis of cerebral malaria may aid in the development of better therapeutic strategies for patients. The immune response in cerebral malaria involves elevation of circulating levels of cytokines and chemokines associated with leukocyte accumulation and breakdown of the blood-brain barrier in the central nervous system. Platelet-activating factor (PAF) is a mediator of inflammation shown to orchestrate inflammatory processes, including recruitment of leukocytes and increase of vascular permeability. Using mice lacking the PAF receptor (PAFR(-/-)), we investigated the relevance of this molecule for the outcome and the neuroinflammatory process triggered by P. berghei ANKA, an experimental model of cerebral malaria. In PAFR(-/-) mice, lethality was markedly delayed and brain inflammation was significantly reduced, as demonstrated by histology, accumulation, and activation of CD8(+) T cells, changes in vascular permeability and activation of caspase-3 on endothelial cells and leukocytes. Similarly, treatment with the PAFR antagonist UK-74,505 delayed lethality. Taken together, the results suggest that PAFR signaling is crucial for the development of experimental cerebral malaria. Mechanistically, PAFR activation is crucial for the cascade of events leading to changes in vascular permeability, accumulation, and activation of CD8(+) T cells and apoptosis of leukocytes and endothelial cells.
Full-text · Article · Nov 2011 · American Journal Of Pathology