Ativação local da rota da quinurenina por moduladores inflamatórios durante a meningite bacteriana.

Activation of the kynurenine (KYN) pathway (KP) by modulators of immune system has been observed during several neurological diseases. Here we assessed the association of chemo-/cytokine levels with the concentration of KP metabolites in cerebrospinal fluid (CSF) and plasma samples from patients with bacterial meningitis (BM). All samples were collected from 42 patients diagnosed with acute bacterial meningitis (ABM), aseptic meningitis, tuberculous meningitis and patients without infection neurological disorders. CSF and plasma concentration of metabolites from the KP was assessed by high pressure liquid chromatography (HPLC) and cytokines and chemokines by Bio-plex 200 suspension array system. Concentrations of the KP metabolites KYN and kynurenic acid (KYNA) were significantly higher in CSF of patients with ABM compared to other groups. Tryptophan (TRP), anthranilic acid (AA), 3-hydroxykynurenine (3HK) and 3-hydroxyanthranilic acid (3HAA) did not show statistical significance, although some of them presented a good accumulation during ABM. The expression of TNF-alpha, IL-6, IL-1beta, IFN-gamma, IL-10, IL-1 receptor antagonist (IL-1Ra), MIP-1alpha, MIP-1beta, MCP-1 and G-CSF was about 100-fold higher in CSF from ABM patients than other infected groups. In all CSF and plasma samples, the concentration of IL-2, IL-12(p70), IL-4, IL-8 and GM-CSF was not significant. ABM still showed significant concentrations of IL-6, IL-10, IL-1Ra and MCP-1 in plasma samples. Based on the comparison of KP metabolites concentrations between plasma and CSF samples we conclude that the activation of the tryptophan pathway upon BM occurs within the brain. This increase in KP metabolites is most due to activation of the KP by molecules as IFN-gamma and TNF-alpha in response to infection.

Efeitos da sinalização via creb sobre a sobrevivência e diferenciação meuronal

The cortical development requires a precise process of proliferation, migration, survival and differentiation of newly formed neurons to finally achieve the development of a functional network. Different kinases, such as PKA, CaMKII, MAPK and PI3K, phosphorylate the transcription factors CREB, and thus activate it, inducing CREB-dependent gene expression. In order to identify the involvement of such signaling pathways mediated by CREB over neuronal differentiation and survival, in vitro experiments of cell culture were conducted using pharmacological kinase inhibitors and genetic techniques to express different forms of CREB (A-CREB and CREB-FY) in cortical neurons. Inhibition of PKA and CaMKII decreased the length of neuronal processes (neurites); whereas inhibition of MAPK did not affect the length, but increased the number of neurites. Blockade of PI3K do not appear to alter neuronal morphology, nor the soma size changed with the kinase blockades. CREB activation (CREB-FY) along with MAPK and PI3K blockades presented a negative side effect over neuritic growth and the expression of A-CREB leaded to a significant decrease in neuronal survival after 60h in vitro and mimicked some of the effects on neuronal morphology observed with PKA and CaMKII blockade. In summary the signaling through CREB influences the morphology of cortical neurons, particularly when phosphorylated by PKA, and CREB signaling is also important for survival of immature neurons prior to the establishment of fully functional synaptic contacts. Our data contribute to understanding the role of CREB signaling, activated by different routes, on survival and neuronal differentiation and may be valuable in the development of regenerative strategies in different neurological diseases

Reprogramming of distinct astroglial populations into specific neuronal subtypes in vitro and in vivo

Recently, the field of cellular reprogramming has been revolutionized by works showing the potential to directly lineage-reprogram somatic cells into neurons upon overexpression of specific transcription factors. This technique offers a promising strategy to study the molecular mechanisms of neuronal specification, identify potential therapeutic targets for neurological diseases and eventually repair the central nervous system damaged by neurological conditions. Notably, studies with cortical astroglia revealed the high potential of these cells to reprogram into neurons using a single neuronal transcription factor. However, it remains unknown whether astroglia isolated from different regions of the central nervous system have the same neurogenic potential and generate induced neurons (iN) with similar phenotypes. Similarly, little is known about the fate that iNs could adopt after transplantation in the brain of host animals. In this study we compare the potential to reprogram astroglial cells isolated from the postnatal cerebral cortex and cerebellum into iNs both in vitro and in vivo using the proneural transcription factors Neurogenin-2 (Neurog2) and Achaete scute homolog-1 (Ascl1). Our results indicate cerebellar astroglia can be reprogrammed into induced neurons (iNs) with similar efficiencies to cerebral cortex astroglia. Notably however, while iNs in vitro adopt fates reminiscent of cortical or cerebellar neurons depending on the astroglial population used for reprogramming, in situ, after transplantation in the postnatal and adult mouse brain, iNs adopt fates compatible with the region of integration. Thus, our data suggest that the origin of the astroglial population used for lineage-reprogramming affects the fate of iNs in vitro, but this imprinting can be overridden by environmental cues after grafting.

Da negatividade a positividade: possível trânsito de saberes, práticas e representações sociais sobre o estigma da hanseníase

Leprosy is a chronic infectious-contagious disease, caused by Mycobacterium leprae, manifested by dermatological and neurological signs and symptoms and has great disabling power. It was marked by a strong stigma throughout its history, since its bearers represented a threat, target of fear and social contempt. Currently, leprosy has treatment and cure, and the need to separate the diseased from family and social environment is no more necessary. However, patients still suffer prejudice and discrimination. This study aimed to understand the social representations of leprosy that interfere modifying mental health of the patient with leprosy in relation to stigma and prejudice. This is a descriptive and exploratory study, with qualitative approach, which involved 22 users of the Special Care Clinic in Infectious Diseases at the Hospital Giselda Trigueiro, located in Natal / RN. They were in use of multidrug therapy in the period of data collection, were of both sexes, aged between 16 and 80 years of age and classified as paucibacillary or multibacillary. The study was approved by the UFRN Ethics in Research Committee. Data collection was performed by filling the questionnaire identification and then for conducting the semi-structured interview, which was recorded. After the end of data collection, there was the construction of tables and graphs, using the Microsoft Excel Start 2010 for proper characterization of the research subjects; and for the treatment of the data obtained from the interviews, was used the Content Analysis and based on the Theory of Social Representations. The subjects studied were mostly male (64%), married or in a stable relationship (68%), concentrated in the age group 50-60 years (36%) and 28-38 years (23%), had at most elementary education (65%) and were low-income (59%). Of the total respondents, 64% were classified as multibacillary, with predominantly dimorfous form, and 50% had disability grade I or II, with different periods of diagnosis. The reports originate two categories: 1. The negative meanings of illness and leprosy; and 2. The positive meanings of illness in leprosy, which were subsequently subdivided into subcategories. Thus, it was found that in the group studied, the social representation of leprosy experiences a moment of transition, as regards the understanding of the disease and its way of experiencing the disease process. Such representation is anchored in the quality of information on the disease of its bearers and aimed at an attempt to face the illness of leprosy as a "normal process". It was found in this study that the transition is due to the work of combating stigma and consequences of leprosy, which is able to gradually transform reality, both regarding the team work of reference, and in relation to a broader character, of actions of health education, which favors overcoming of psychosocial disabilities