L'interleukine-6 (IL-6) est une cytokine associée aux maladies auto-immunes de la glande thyroïde et qui pourrait aussi avoir un rôle dans le développement de l'hypertrophie cardiaque pathologique. Dans les cellules thyroïdiennes FRTL-5 et dans les cardiomyocytes de rats adultes, nous montrons que la sécrétion et l'expression de l'ARNm de l'IL-6, stimulées par l'interleukine-1 (IL-1), sont augmentées de manière synergique par la voie de l'AMPc/PKA. Dans les cellules FRTL-5, cet effet synergique s'exerce aussi au niveau de l'activation du promoteur de l'IL-6 et implique les sites AP-1 et CRE ainsi que les facteurs de transcription c-Fos et Fra2. L'IL-6 et son récepteur membranaire stimulent les voies de signalisation impliquant STAT3 et ERK-5 dans les cellules FRTL-5. Dans les cardiomyocytes, STAT3 est activé par l'IL-6 uniquement en présence de son récepteur soluble. Nous montrons que ce mécanisme de conduit à la stimulation de marqueurs associés au processus hypertrophique pathologique.

<p>Objective - To correlate blood pressure and inflammatory markers with urine albumin analysed with a point-of-care testing (POCT) instrument, nephelometric determination of albumin and creatinine related urine albumin in elderly males.</p><p>Methods and Results - The study population consisted of 103 diabetic and 603 nondiabetic males (age 77 years) in a cross-sectional study in central Sweden. We analyzed urine albumin with a HemoCue® Urine Albumin POCT instrument and a ProSpec® nephelometer and creatinine related urine albumin. There were strong correlation between both systolic and diastolic blood pressure and all three urine albumin methods (p<0.0001). There were also significant correlations between the different urine albumin measurements and SAA, hsCRP and IL-6.</p><p>Conclusions - Hypertension has a strong impact on hyperfiltration in diabetic and nondiabetic elderly males.</p>

The aims were to investigate oxidative stress (I), angiogenesis (II) and inflammation (III-IV) in healthy women during pregnancy and postpartum. Oxidative stress was estimated by measurement of 8-iso-PGF2α and the antioxidants α- and γ-tocopherol. The angiogenic factors PlGF, VEGF-A and the antiangiogenic factor sFlt1 were measured to estimate angiogenesis. PTX3, IL-6, TNF-α and a PGF2α metabolite were measured to estimate inflammation. Out of 52 included women, 15 had minor pregnancy complications and 37 were classified as normal. In study III data from all 52 women were used. For the other studies (I, II and IV) only data from the 37 women with normal pregnancy were used. Pregnancy was associated with increased levels of 8-iso-PGF2α with advancing gestational age. The median postpartum value corresponded to values observed in early gestation and a significant decrease was observed from late pregnancy to postpartum. Lipid-adjusted α- and γ-tocopherol levels decreased with advancing gestational age (I). PlGF increased from early pregnancy until weeks 29–30 and thereafter decreased until week 40. sFlt1 levels were relatively constant until weeks 29–30, when they increased, reaching a peak at weeks 39–40. Postpartum levels were low. The sFlt1:PlGF ratio decreased from weeks 9–12, was constantly low from weeks 19–20 to 37–38 and then increased to weeks 39–40. VEGF-A was detectable in only 8 % of the samples during pregnancy and in 64 % postpartum (II). There was a continuous increase of PTX3 as pregnancy progressed. The increase was most evident after week 31 with the highest levels just before delivery (III). IL-6 increased throughout pregnancy and remained high postpartum. No change in TNF-α could be seen with advancing gestational age or postpartum. The PGF2α metabolite levels increased throughout pregnancy and decreased postpartum (IV). In conclusion, normal pregnancy is associated with mild oxidative stress and inflammation. This might have physiological effects for normal pregnancy development. By delineating how these mediators of oxidative stress, angiogenesis and inflammation fluctuate throughout normal pregnancy and postpartum, we have established a reference for studies of these factors in pregnancy complications.

Objective - To correlate blood pressure and inflammatory markers with urine albumin analysed with a point-of-care testing (POCT) instrument, nephelometric determination of albumin and creatinine related urine albumin in elderly males. Methods and Results - The study population consisted of 103 diabetic and 603 nondiabetic males (age 77 years) in a cross-sectional study in central Sweden. We analyzed urine albumin with a HemoCue® Urine Albumin POCT instrument and a ProSpec® nephelometer and creatinine related urine albumin. There were strong correlation between both systolic and diastolic blood pressure and all three urine albumin methods (p&lt;0.0001). There were also significant correlations between the different urine albumin measurements and SAA, hsCRP and IL-6. Conclusions - Hypertension has a strong impact on hyperfiltration in diabetic and nondiabetic elderly males.

Lors d'un exercice physique prolongé, les muscles produisent et libèrent de l'interleukine-6 (IL-6). Cette production est corrélée à l'intensité de l'exercice et à la baisse des réserves musculaires en glycogène. L'IL-6 agirait par voie endocrine en favorisant la production endogène de glucose par le foie.<br />Notre premier objectif était d'étudier le contrôle de l'expression du gène IL-6 dans le muscle squelettique à l'exercice chez le rat et plus particulièrement l'importance de la voie de signalisation de la calcineurine, activée par la contraction musculaire. Nous avons d'abord montré que la transcription du gène IL-6 avait lieu dans les fibres musculaires oxydatives (I et IIa) et était associée à une activité importante de la voie de la calcineurine. Nous avons ensuite montré que l'administration d'inhibiteurs pharmacologiques de la calcineurine (ciclosporine A ou FK506) diminuait significativement la transcription du gène IL-6 dans les muscles lents/oxydatifs, prévenant ainsi l'apparition de la protéine dans le plasma. Nous avons ainsi démontré l'implication de la voie de la calcineurine dans le contrôle du gène codant IL-6 dans le muscle en réponse à un exercice unique. <br />Notre deuxième objectif était d'étudier l'action d'IL-6 sur le foie à l'exercice, plus particulièrement sur le contrôle du gène codant une enzyme clé de la néoglucogenèse, la phosphoenolpyruvate carboxykinase (PEPCK). Nous apportons des arguments expérimentaux en faveur d'un effet direct d'IL-6 sur le tissu hépatique et d'un contrôle possible de la transcription du gène codant PEPCK par l'IL-6 circulante. D'autre part nous suggérons l'implication d'acteurs moléculaires nouveaux, Peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α) et Farnesoid X receptor (FXR), dans le contrôle de la néoglucogenèse à l'exercice.

L’interleukine 6 (IL-6) est une cytokine qui joue un rôle essentiel dans l’inflammation. Son récepteur (IL-6R) est composé de la chaîne non signalétique IL-6Rα et de la chaîne transductrice du signal gp130, commune aux cytokines de la famille IL-6. La liaison de l’IL-6 à son récepteur permet l’activation de plusieurs voies de signalisation, notamment des voies Jak/STAT1 et préférentiellement Jak/STAT3. De façon complémentaire, nous avons démontré que l’IL-6 est capable d’activer la voie Jak/STAT5 dans les lymphocytes T CD4. L’activation de cette voie de signalisation pourrait être impliquée dans le rétrocontrôle des effets pro-inflammatoires de l’IL-6 sur les cellules T CD4. Le facteur neurotrophique ciliaire (CNTF) et la « cardiotrophin-like cytokine/cytokine-like factor 1 » (CLC/CLF) sont deux cytokines de la famille de l’IL-6 qui signalent à travers un récepteur commun, le récepteur au CNTF (CNTFR), composé du CNTFRα, « leukaemia inhibitory factor receptor β » (LIFRβ) et gp130. Toutes deux exercent des actions au niveau du système immunitaire, or la chaîne CNTFRα de leur récepteur n’y est pas exprimée. Il a été montré que le CNTFR humain peut également activer un récepteur formé des sous-unités IL-6Rα, LIFRβ et gp130. Nous avons comparé les effets du CNTF et du CLC/CLF de souris sur des transfectants exprimant LIFRβ et gp130 et les chaines α connues de la famille IL-6 (IL-6Rα, IL-11Rβ et CNTFRα). Nos résultats indiquent que le CNTF de souris, comme le CNTF humain est capable d’activer un récepteur formé de l’IL-6Rα, LIFRβ et gp130. Toutefois cette propriété n’est pas partagée par CLC/CLF et le récepteur impliqué dans les effets de cette cytokine sur le système immunitaire reste donc à identifier. L’IL-27 appartient à la famille de l’IL-6 composée d’une sous-unité cytokinique, p28, associée à un récepteur soluble « l’Epstein-Barr virus-induced gene 3» (EBI3). La sous-unité p28 peut s’associer avec le récepteur soluble CLF pour former une cytokine capable d’activer les lymphocytes T. Dans le but de caractériser cette cytokine, nous avons montré que p28/CLF agit aussi sur les lymphocytes B et permet leur différenciation en plasmocytes. Le partage de l’IL-6R par l’IL-6 et p28/CLF semble être à l’origine de la similarité des effets de ces deux cytokines. De plus, nous avons observé des effets semblables à ceux de l’IL-6 suite à l’association de la sous-unité p28 seule avec la chaîne IL-6Rα. En effet, afin de mieux caractériser la cytokine p28/CLF, nous avons étudié les effets dus au recrutement de la chaîne IL-6Rα par la sous-unité p28. Les cytokines de la famille de l’IL-6 sont composées de quatre hélices α disposées de façon anti-parallèle deux à deux. La sous-unité p28 possède, au niveau d’une boucle reliant deux hélices α, un motif de plusieurs acides glutamiques consécutifs (motif polyE) qui n’est retrouvé dans aucune autre cytokine de cette famille. Nous avons démontré que ce motif est impliqué dans la liaison de cette sous-unité avec l’hydroxyapatite et l’os. Cette caractéristique de p28 pourrait permettre un ciblage de l’IL-27 (p28/EBI3) et de p28/CLF préférentiellement vers la niche endostéale des cellules souches et des cellules immunitaires. / Interleukin 6 (IL-6) is a well known cytokine, characterized for its essential function in inflammation. IL-6 receptor (IL-6R) is composed of IL-6Rα, an unsignalling chain, associated with the signaling transducing chain gp130. This glycoprotein is shared by all IL-6 family cytokines. After binding with its receptor, IL-6 preferentially induces the activation of the Jak/STAT3 pathway but can also activate the Jak/STAT1 pathway. Unexpectedly we demonstrated that IL-6 can activate the Jak/STAT5 pathway in CD4 T cells. This STAT5 could act as negative feedback mechanism in response to the pro-inflammatory effects induced by an excess of IL-6. Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC/CLF) both belong to the IL-6 cytokine family and share the same receptor, the CNTF receptor (CNTFR). CNTFR is composed of CNTFRα, leukaemia inhibitory factor receptor β (LIFRβ) and the glycoprotein gp130. Interestingly, the CNTFRα chain is not expressed by immune cells even though CNTF and CLC/CLF are active on these cells. These effects can be due to the formation of a complex between cytokine and CNTFRα, which can be shedded. This complex can then activate cells expressing only gp130 and LIFRβ. In human, it has been demonstrated that the CNTFRα chain can be substitute with IL-6Rα. Here, we compare mouse CNTF- and CLC/CLF-induced effects in transfected cells expressing LIFRβ, gp130 and different α chains belonging to the IL-6 family (IL-6Rα, IL-11Rα or CNTFRα). Our data demonstrate that like human CNTF, mouse CNTF is able to activate a receptor comprising of IL-6Rα, gp130 and LIFRβ. However, this property is not shared with CLC/CLF. Therefore, second receptor for this cytokine within the immune system still remains to be identify. Interleukin 27 (IL-27) belongs to the IL-6 cytokine family and is composed of the cytokine subunit p28 associated with a soluble receptor chain Epstein-Barr virus-induced gene 3 (EBI3). We demonstrate that the p28 subunit can bind the soluble receptor CLF to form a new dimeric cytokine named p28/CLF. This cytokine is active on T cells and our study demonstrates its activity on B cells. Our results show that p28/CLF sustains plasma cell differentiation. Those IL-6-like properties can be explained by the use of a common receptor, IL-6R. Moreover, our findings demonstrate that p28 has IL-6-like properties when associated with IL-6Rα. In order to better characterize p28/CLF, we next studied effects of to the recruitment of the IL-6Rα chain by p28 subunit. Cytokines belonging to the IL-6 family share a structural particularity by forming a four helix bundle cytokines family. The p28 subunit uniquely expresses a motif composed of a dozen of glutamic acids (polyE motif). We demonstrate that this motif permits p28 binding to hydroxyapatite and bone matrix. This observation could allow a preferential targeting to bone of IL-27 (p28/EBI3) and p28/CLF, and specifically a targeting of stem or immune cells to endosteal niches.

The immune system has been suggested as crucial in brain and psychological functioning. More precisely, immune markers reflecting immune system activity are important for psychological and mental health, as evident by their role in the physiopathology of depression and in the impairment of executive functions. Frontal alpha asymmetry (FAA), an electroencephalographic marker of brain function, has also been linked to such psychopathology and is thought to reflect psychological processes underlying approach- versus withdrawal-related motivation and higher-order inhibitory control. Only a few studies have linked FAA to immune markers but notably found a negative association between IL-6, a pleiotropic pro-inflammatory cytokine, and FAA. The aim of the present work is thus to study the relationship between various immune markers (including pro-inflammatory cytokines and IL-6) and FAA. 35 healthy young male participants underwent a resting EEG recording and blood sampling from which immune markers were measured. The results did not suggest an association between IL-6 and FAA. No other immune markers were either suggested to be associated to FAA. The complexity of the immune system (e.g., effect of cytokines) is underlined and may explain the results. Despite such results, the implication of true negative correlations between FAA and circulating immune markers, as suggested in previous studies, is discussed in the light of the theoretical models of FAA.

Submitted by Pós Imunologia (ppgimicsufba@gmail.com) on 2017-02-20T18:12:18Z No. of bitstreams: 1 OLIVEIRA RC-2015.pdf: 1350637 bytes, checksum: b7f46beea8a9ab0be171a19ce556fa7f (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2017-06-14T13:28:00Z (GMT) No. of bitstreams: 1 OLIVEIRA RC-2015.pdf: 1350637 bytes, checksum: b7f46beea8a9ab0be171a19ce556fa7f (MD5) / Made available in DSpace on 2017-06-14T13:28:00Z (GMT). No. of bitstreams: 1 OLIVEIRA RC-2015.pdf: 1350637 bytes, checksum: b7f46beea8a9ab0be171a19ce556fa7f (MD5) / Fapesb / O lúpus eritematoso sistêmico (LES) é uma doença reumática autoimune que pode acometer uma em cada 1.700 mulheres brasileiras. Trata-se de doença cuja etiologia se fundamenta na associação da predisposição genética dos pacientes com fatores ambientais e hormonais, perda da tolerância imunológica e propagação da autorreatividade inata e adaptativa, resultando em manifestações clínicas complexas e multivariadas. Diversos aspectos associados com a atividade do LES, especialmente a doença renal presente em importante proporção dos pacientes, têm sido objeto de intensa investigação. Entre estes, a participação de autoanticorpos e a contribuição de componentes bioativos como citocinas e hormônios na nefrite lúpica ocupam posição de destaque. Objetivo: No presente estudo foi investigada a participação dos anticorpos anti-dsDNA totais e de alta avidez, antinucleossomo (ANuA) e hiperprolactinemia na atividade do LES e nas suas manifestações clínicas com destaque para Artropatia de Jaccoud, usando como população alvo mulheres lúpicas residentes na Bahia. Material e Métodos: Cento e quarenta e duas mulheres portadoras de LES foram investigadas para a prevalência e níveis de anticorpos anti-dsDNA totais, anticorpos anti-dsDNA de alta avidez e ANuA, além de hiperprolactinemia. Adicionalmente, foram testadas as correlações dos níveis destes componentes com a atividade da doença e suas associações com as manifestações clínicas mais prevalentes nestas pacientes. Autoanticorpos antinucleares foram determinados por testes de imunofluorescência indireta e ELISA. Níveis séricos de prolactina e citocinas foram determinados por imunoensaios de captura de antígeno, enquanto os níveis de C3 e C4 foram determinados por imunonefelometria. Os níveis de creatinina e proteinúria foram medidos por métodos colorimétricos e a atividade lúpica avaliada com o protocolo SLEDAI-2K. Testes de estatística univariada foram usados nas análises dos resultados. Resultados: Os níveis de anticorpos anti-dsDNA de alta avidez e de anti-dsDNA totais se correlacionaram diretamente com os níveis de anticorpos antinucleossomo, sendo esta correlação mais forte com os primeiros. Correlações significativas entre os níveis de C3, C4, VHS, proteinúria e SLEDAI foram observadas com os níveis de anticorpos anti-dsDNA de alta avidez e, exceto proteinúria, com os níveis de ANuA. Os níveis de anticorpos anti-dsDNA totais se correlacionaram apenas com os níveis de C3 e SLEDAI, porém de forma menos significativa que os anticorpos anti-dsDNA de alta avidez e ANuA. Pacientes com artropatia de Jaccoud apresentaram níveis mais altos de anticorpos antidsDNA totais e IL-6. Hiperprolactinemia leve a moderada foi encontrada em 19,7% das pacientes, observando-se níveis séricos de prolactina mais altos nas pacientes com comprometimento renal, além de existir correlação entre os níveis séricos deste hormônio com os níveis de creatinina sérica e proteinúria. Adicionalmente, existiu uma aparente supressão da produção de anticorpos anti-RNP- 70 em pacientes lúpicas hiperprolactinêmicas com fenômeno de Raynaud. Conclusões: Anticorpos anti-dsDNA constituem-se em importantes biomarcadores de doença ativa em pacientes portadoras de LES residentes na Bahia, podendo complementar o diagnóstico da artropatia de Jaccoud nestas pacientes, além de sugerir a presença de comprometimento renal quando são de alta avidez e detectados conjuntamente com proteinúria e baixos níveis de C3. Por outro lado, a presença de uma hiperprolactinemia leve a moderada pode ser verificada nestas mulheres, cujo envolvimento na doença renal lúpica foi demonstrado neste estudo, além de inibir a produção de anticorpos anti- RNP-70. / Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that affect one in 1,700 Brazilian women. This disease is associated with a genetic predisposition of the patients and has the contribution of hormonal and environmental factors. Lupus' patients have a loss of immune tolerance, resulting in uncontrolled autoimmune reactivity and complex and multivariate clinical manifestations. Various aspects associated with the activity of SLE, especially kidney disease, have been the subject of intense investigation. Among these, the participation of autoantibodies and the contribution of bioactive components such as cytokines and hormones occupy a prominent position in these studies. Objective: The present study investigated in SLE women who lived in Bahia (Brazil), the participation of total and high avidity dsDNA, antinucleosome antibodies (ANuA) and hyperprolactinemia in the activity of this disease and its clinical manifestations, especially arthropathy of Jaccoud. Material and Methods: One hundred and forty-two women with SLE were investigated for the presence of hyperprolactinemia and prevalence and levels of total and high avidity anti-dsDNA antibodies and ANuA. Correlations among these components with biomarkers of lupus activity and their associations with the most prevalent clinical manifestations in the patients were also tested. Indirect fluorescent antibody test and ELISA determined antinuclear autoantibodies. Capture immunoassays measured prolactin and cytokine levels while C3 and C4 levels were determined by immunonephelometric tests. Creatinine levels and proteinuria were measured by colorimetric methods and lupus activity assessed with the SLEDAI-2K protocol. Descriptive statistical tests were used in the analyses of the results. Results: The levels of both high avidity and total anti-ds DNA antibodies correlated directly with the levels of antinucleosome antibodies, but this correlation was stronger with dsDNA antibodies of high avidity. Significant correlations among the levels of C3, C4, ESR, proteinuria and SLEDAI were observed with the levels of anti-dsDNA antibodies of high avidity and, except proteinuria, with ANuA levels. The levels of total anti-dsDNA antibodies correlated only with levels of C3 and SLEDAI, but these correlations were lesser than those of high avidity dsDNA antibodies and ANuA. Patients with Jaccoud arthropathy presented higher levels of dsDNA antibodies and IL-6, whereas mild to moderate hyperprolactinemia was found in 19.7% of the lupus patients. Higher serum levels of prolactin were demonstrated in patients with kidney disease, as well as there was a correlation between the levels of this hormone with their serum levels of creatinine and urine protein. In addition, hyperprolactinemia seems to inhibit the production of anti-RNP-70 autoantibodies. CONCLUSIONS: Antibodies to dsDNA are important biomarkers of active disease in SLE patients from Bahia and the increase in dsDNA antibody levels can complement the diagnosis of Jaccoud’s arthropathy. In addition, high avidity dsDNA autoantibodies are a good laboratory evidence of renal impairment in lupus patients when they are detected together with proteinuria and low levels of C3. On the other hand, the presence of a mild to moderate hyperprolactinaemia can be seen in lupus women whose involvement in lupus kidney disease and inhibition of the production of RNP-70 autoantibodies was demonstrated in this study.

A morfina é um analgésico eficaz e muitas vezes opioide usado para aliviar a dor moderada a grave durante o período neonatal precoce. A exposição repetida de morfina no início da vida tem implicações duradouras para o desenvolvimento do sistema nervoso, tais como alterações neuroquímicas e comportamentais a longo prazo em ratos. O exercício físico vem sendo utilizado como uma alternativa não farmacológica para tratamento de quadros dolorosos. Deste modo nosso objetivo foi avaliar o efeito da exposição a morfina no período neonatal nas respostas nociceptiva (térmica e mecânica) e bioquímicas (citocinas e neurotrofinas) em ratos de P30 e P60 antes e após a exposição ao exercício físico. Ratos Wistar com 7 dias foram divididos em dois grupos: salina (SA) e morfina (MO) e submetidos a 5 mg / dia / 7 dias P8 para P14 a soro fisiológico ou MO respectivamente. Nas idades de P16, P30 e P60 a resposta nociceptiva térmica foi avaliada através do teste da placa quente (PQ), a resposta mecânica por Von Frey (VF) e Randal e Selitto (RS). Ainda foram medidos os níveis basais de BDNF, NGF, IL-6 e IL-10 em córtex cerebral e tronco encefálico. Após a sessão de exercício foram realizados em P30 e P60 o teste de PQ, 1h e 24h após o exercício, o teste de VF foi realizado 24h após e os níveis de BDNF, NGF, IL-6 e IL-10 também foram medidos em córtex cerebral e tronco encefálico após a exposição ao exercício. Nossos resultados demonstram que os animais que receberam morfina no período neonatal apresentam diminuição do limiar nociceptivo térmico e mecânico em P30 e P60. Os níveis de BDNF, NGF, IL-6 e IL-10 apresentaram relação direta com a idade em tronco encefálico, aumento ao longo do tempo. Em córtex cerebral os níveis de BDNF e NGF demonstraram uma interação entre os fatores grupo e idade, onde os animais do grupo MO têm diminuição desses com a idade. A IL-10 teve efeito somente da idade, enquando a IL-6 não se mostrou alterada por nenhum fator. Após a exposição ao exercício no teste da PQ no P30 e P60 os animais SAE tiveram uma diminuição do limiar nociceptivo se igualando aos grupos que receberam morfina. No teste de VF em P30 os grupos que receberam morfina são diferentes do grupos salina. Em P60 o grupo SAE mostra mais uma vez diminuiçao do limiar nociceptivo se igualando as grupos morfina. Nos níveis de BDNF e NGF em tronco encefálico ocorreu interação entre idade e grupo, onde o grupo MOE demonstra diminuição. Em tronco encefalico a IL-6 e Il-10 só tiveram efeito da idade. Em córtex cerebral os níveis de BDNF tiveram interação entre idade e grupo, o grupo MOE teve diminuição destes níveis em comparação aos demais grupos. Nos níveis de NGF se observou efeito do tempo e do grupo onde os grupos que recebem morfina têm níveis menores do que os que recebem salina em P60. O grupo MOS teve níveis menores de IL-6 em cortex cerebral do que os demais grupos, enquanto que os níveis de IL-10 só tiveram efeito da idade. Portanto a morfina no período neonatal leva a diminuição no limiar nociceptivo térmico e mecânico em ratos e que o exercício físico melhora os níveis BDNF, NGF e IL-6 em animais expostos a morfina no período neonatal. Porém o exercício físico não foi capaz de reverter a hiperalgesia e alodínia induzida pela morfina nos animais de P30 e P60. Sendo assim nossos dados mostram a necessidade de mais estudos sobre a dor em recém-nascidos e o sobre o uso de opioides neste período. Também se mostra necessário mais estudos sobre tratamentos não farmacológicos como o exercício físico. / Morphine is an effective analgesic often used to relieve moderate to severe pain during the early neonatal period. In our previous study, repeated morphine exposure in early life triggered persistent implications for the development of the nervous system, such as neurochemical and behavioral alterations in rats at long-term. The exercise has been used as a non-pharmacological alternative for treating painful conditions. Thus our aim was to evaluate the effect of repeated morphine exposure during the neonatal period upon nociceptive responses (thermal and mechanical) and biochemical markers (cytokines and neurotrophins) before and after unique physical exercise session in rats at P30 and P60. Seven-day-old male Wistar rats were divided into two groups: saline and morphine and subjected to saline and morphine (5 μg/day/7 days) from P8 to P14, respectively. At P16, P30 and P60, the thermal nociceptive response was assessed using the hot plate test (HP), while the mechanical response by Von Frey (VF) and Randal and Selitto (RS) tests. The basal levels of BDNF, NGF, IL-6 and IL-10 were measured in brainstem and cerebral cortex. One hour and 24h after exercise, the HP was conducted in P30 and P60, the VF test was only performed 24 ho after exercise, as well as the levels of BDNF, NGF, IL-6 and IL-10 were also measured in cerebral cortex and brainstem. Our results show that rats that received morphine in the neonatal period presented decreased thermal and mechanical nociceptive threshold in P30 and P60. And, BDNF, NGF, IL-6 and IL-10 levels presented a direct relationship with age in brainstem, increase their levels when the age increased. In cerebral cortex, BDNF and NGF levels showed an interaction between age and treatment group, where the morphine group showed decreased levels when the age increased. There was age effect upon IL-10 levels and no effects upon IL-6 levels in cerebral cortex. After 24h of exercise, saline group subjected to exercise presented decreased nociceptive threshold in using HP at P30 and P60, with similar threshold presented by morphine group. In VF test, both morphine groups presented decreased threshold in relation to both saline groups at P30. However, at P60, saline group subjected to exercise presented decreased nociceptive threshold, matching the morphine groups. In brainstem, we found interaction between age and group in BDNF and NGF levels, where morphine-exercise group showed decreased levels; and we observed only age effect upon IL-6 and IL-10 levels. In cerebral cortex, we observed interaction between age and group upon BDNF levels, where morphine-exercise group showed decreased levels compared to other groups. In relation to NGF levels, we observed effect of age and group, where morphine groups presented lower levels than saline groups in P60. The morphine-sedentary group presented lower IL-6 levels in the cerebral cortex than the other groups, while only age effect was observed on IL-10 levels. Our data lead us to conclude that morphine exposure in the neonatal period triggers a decrease in thermal nociceptive and mechanical thresholds in rats. And, the physical exercise improves BDNF, NGF and IL-6 levels in rats exposed to morphine in the neonatal period. However, on session of exercise was not able to revert the hyperalgesia and allodynia induced by morphine in rats at P30 and P60. Therefore, our data highlight the need of more studies about pain in newborns and neonates and the effect of the opioid use in this period. And, it is necessary more studies about non-pharmacological treatments, for example exercise.

Introdução: A Doença de Alzheimer (DA) é uma desordem neurodegenerativa e a forma mais comum de demência. Processos inflamatórios parecem desempenhar importante papel na fisiopatologia da DA. A neuroinflamação é caracterizada pela ativação da microglia e a liberação de citocinas inflamatórias, tais como IL-1β, IL-6 e TNF-α. Porém, não se sabe qual é a real contribuição destes marcadores inflamatórios no desenvolvimento da DA. Objetivos: A proposta deste estudo é avaliar a possível relação entre marcadores inflamatórios no liquido cefalorraquidiano de indivíduos com comprometimento cognitivo leve amnéstico (CCL-a), com 60 anos ou mais, e comparar com controles saudáveis da mesma faixa etária. Métodos: Foram examinadas as concentrações de IL-1β, IL-6 e TNF-α no líquido cefalorraquidiano de sujeitos com CCL-a e em controles pelo método ELISA. Diagnósticos de CCL-a foram baseados na anamnese e nos critérios de Petersen, corroborados pela escala CDR. Para avaliar a função cognitiva o teste de memória e reconhecimento de palavras do CERAD e o Teste do Relógio foram aplicados aos participantes. Para a avaliação de sintomas depressivos usou-se o GDS. Resultados: Este estudo demonstrou diminuição significativa nos níveis de IL-1β (13.735 vs 22.932 pg/mL; p <0.001) e TNF-α (1.913 vs 2.627 pg/mL; p: 0.002), mas não nos níveis da IL-6 (4.178 vs 5.689 pg/mL; p: 0.106), entre casos e controles. Indivíduos com IL-1β < 17 pg/mL possuem 7.2 (CI: 1.5-36; p: 0.016) mais chances de evoluírem à CCL-a. Além disso, houve correlação positiva entre IL-1β e a pontuação da lista de palavras do CERAD (rs: 0.299; p: 0.046). A análise de regressão linear mostrou que os níveis de IL-1β podem explicar 13.7% (β: 24.545; p: 0.012) da variância da pontuação do CERAD, o que sugere uma dependência linear direta. Conclusões: A neuroinflamação, mediada pela IL-1β e pelo TNF-α, provavelmente possui importante papel na prevenção de CCL-a. / Introduction: Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of dementia. Inflammatory processes may play a significant role at the pathophysiology of AD. Neuroinflammation is characterized by activation of microglia and the release of inflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Although, it is unknown what is the real contribution of these inflammatory markers in the development of AD. Aims: The purpose of this study is to assess the possibly relationship between inflammatory markers in CSF of amnestic MCI subjects, with sixty years or older, and compare to aged healthy controls. Methods: We examined concentrations of IL-1β, IL-6 and TNF-α at CSF of amnestic MCI subjects and controls by ELISA. MCI diagnoses were based on anamnesis and Petersen criteria, corroborated by CDR. To assess the cognitive function the word list memory test and word recognition of CERAD and Clock Drawing Test were applied to subjects, and to evaluated depression symptoms the GDS was used. Results: This study demonstrated significant diminish in the levels of IL-1β (13.735 vs 22.932 pg/mL; p <0.001) and TNF-α (1.913 vs 2.627 pg/mL; p: 0.002), but not IL-6 (1.913 vs 2.627 pg/mL; p: 0.002), between cases and controls. Individuals with IL-1β < 17 pg/mL were at a 7.2 (CI: 1.5-36; p: 0.016) increased odds of aMCI. Furthermore, there was a positive correlation between IL-1β and the CERAD word list score (rs: 0.299; p: 0.046). The linear regression analysis showed that IL-1β levels can explain 13.7% (β: 24.545; p: 0.012) of the variance on this CERAD subscore, suggesting a direct linear dependence. Conclusion: Neuroinflamation mediated by IL-1β and TNF-α may play an important role in preventing aMCI.