Brain tumors are the second leading cause of cancer deaths in young adults ages 20- 39. (Armstrong et al., 2004) According to the South African Medical Research Council, there was an estimate 801 deaths because of brain cancer in South Africa in 2000. If these statistics are compared to other types of cancers like breast-, lung- and prostate cancers, is the prevalence of the diagnoses of brain tumors, a very small percentage. According to the Mayo clinic in South Africa, the estimate number of brain tumor incidences was 3% in 2007. Despite of these statistics with regards Brain tumors, one in six South African men and one in seven South African women will be diagnosed with cancer during their life times. Despite this small percentage, the diagnoses of brain tumors have escalated the last few years. The reason for these new statistics is still unknown. With exercise that is becoming one of the most important adjuvant therapies for most diseases or illnesses, we may sustain this idea of using exercise intervention as an adjuvant therapy for brain tumor cancers we can prove this through many researches that has been done in the last few years. (Schwartz, 2003) Studies done by different researchers they found that exercise intervention is becoming increasingly recognized as a safe, feasible and beneficial supportive therapy for cancer patients both during and after the cessation of adjuvant therapy. (Jones et al., 2006) Exercise influences a lot of different systems in the body, to the advantage of the cancer patient (Schwartz, 2003) and emerging new research shows that physical exercise may boost brain function, which include improve mood. (Kong, 1999) Exercise, according to Cotman and Berchtold (2002) is commonly believed to be a behavioral strategy to relieve stress, and reduce depression and anxiety in humans. Exercise intervention further influence following aspects of the human body, namely brain deprived neurotrophic factor (BDNF) and 5-HT (Serotonin). Improvement of these could, in fact, lead to a better quality of life (QoL) of a brain tumor patient (Cotman&Berchtold, 2002). Fatigue that sets in, due to the different cancer therapies, is also a factor that has an affect on depression and anxiety of the patient. Keeping still and rest to prevent fatigue were followed in previous regiment when working with cancer patients was followed. This approach, in fact, has a very negative effect on the patient. Being diagnosed with a brain tumor the patient will never be emotionally prepared for this type of information and it usually shatters their sense of well being and their personal security. All of these factors, especially depression, affect the patient’s QoL. (Vaynman et al., 2004) An exercise regiment for brain tumor patients has not yet been developed properly, because exercise intervention for familiar cancers could be problematic and not suitable for brain tumor patients. (Schwartz, 2003) Therefore, the purpose of this study is to further the knowledge and the field of expertise of exercise as an adjuvant therapy in brain tumor patients to better QoL over a larger period of time. AFRIKAANS : Die tweede grootste leier in siektes tussen die ouderdomme van 20-39 jaar wat lewens eis is Brein gewasse (brein kanker). (Armstrong et al., 2004) Volgens die Suid- Afrikaanse Mediese Navorsingraad, is daar tot 801 gevalle van breingewas sterftes in die jaar 2000 aangemeld. As hierdie statistieke vergelyk word met statistieke van kanker wat meer prominent voorkom soos byvoorbeeld bors-, long-, en protaatkanker, lyk die voorkoms van breinkanker diagnosis maar na ‘n baie klein persentasie. Die Mayo Kliniek in Suid-Afrika het in 2007 bevind dat die voorkoms van breinkanker in Suid-Afrika ‘n persentasie van 3% uitgemaak het. Ten spyte van hierdie statistieke betreffende breingewasse, sal een uit elke ses mans en een uit elke sewe vroue, gediagnoseer word met een of ander kanker gedurende hulle leeftyd. Alhoewel die persentasie wat reeds genoem is maar na ‘n klein hoeveelheid lyk, het die voorkoms van breingewasse baie toegeneem in die laaste paar jaar en selfs maande. Die rede vir hierdie aansienlike toename is steeds onbekend. Oefening word al hoe belangriker en word al hoe meer deur verskeie dokters voorgeskryf om te dien as ‘n bykomende behandeling vir verskeie siekte toestande. Dit word veral ook vir kanker pasiënte voorgeskryf. Oefen intervensie kan dus gebruik word vir breinkanker pasiënte, hierdie stelling gestaaf kan word, aangesien daar verskeie navorsings reeds bewys het dat oefening as bykomende terapie gebruik is vir kanker pasiënte. (Schwartz, 2003) Hierdie studies het bevind dat oefening as ‘n veilige, uitvoerbare en voordelige bykomende intervensie vir kanker pasiënte erken word. Hierdie intervensie kan tydens en na hoof kanker behandeling gebruik word (Jones et al., 2006). Oefening beinvloed verskeie sisteme in die liggaam, tot voordeel van die kanker pasiënt. (Schwartz, 2003) Nuwe navorsing het ook aan die lig laat kom dat fisieke aktiwiteit ‘n persoon se breinfunksie bevorder, wat onder andere ‘n baie groot invloed het om die pasiënt se gemoedstoestand. (Kong, 1999) Volgens, Cotman and Berchtold (2002), is daarvolgens studies bewys dat oefenterapie ‘n manier is om stres te verlig, sowel as depressie en angstigheid in meeste mense. Oefenterapie beinvloed ook die volgende aspekte positief in die menslike liggaam naamlik, Brein ontnemende neurtrofiese-faktor (BDNF) en 5-HT (Serotonien). Verbetering van hierdie faktore, kan ly tot ‘n beter kwaliteit van lewe van ‘n pasiënt wat met ‘n breingewas gediagnoseer is (Cotman&Berchtold, 2002). Uitputting (moegheid) wat gewoonlik intree as gevolg van kanker terapie, is ook ‘n faktor wat ‘n effek het op die depressie- en angsvlakke van ‘n pasiënt. In vroeë behandelingsprotokol van kankerpasiënte, moes die pasiënt so stil as moontlik verkeer om sodoende uitputting of moegheid te voorkom. Hierdie benadering het in die uiteinde ‘n baie negatiewe effek op die pasiënte tot gevolg gehad. ‘n Persoon wat met ‘n breingewas gediagnoseer word sal nooit emosioneel voorbereid wees op hierdie diagnose nie en sodoende kan dit lei tot ‘n ineenstorting van die persoon se geestestoestand en persoonlike sekuriteit. Hierdie “ineenstorting” kan ‘n groot invloed hê op die kwaliteit van lewe van hierdie pasiënt (Vaynman et al., 2004). ‘n Oefenintervensie protokol vir breinkanker pasiënte is nog nie voldoende vasgestel nie, aangesien oefenterapie intervensies wat vir bekende kankers problematies en selfs gevaarlik kan wees vir breingewas pasiënte nie. (Schwartz, 2003) Daarom is die doel van die studie, om inligting te verkry en kennis in te samel om die veld van deskundiges uit te brei om sodoende ‘n oefenterapie protokol neer te lê vir breinkanker pasiënte. Hierdie protokol sal dus dien as ‘n bevordering van kwaliteit van lewe van hierdie pasiente deur middel van oefen intervensie as bykomende behandeling. Copyright / Dissertation (MA)--University of Pretoria, 2012. / Biokinetics, Sport and Leisure Sciences / unrestricted

Le traumatisme crânio-cérébral (TCC) pédiatrique représente l'une des causes principales de handicap chez les enfants à travers le monde. Parmi la gamme de conséquences documentées suite au TCC pédiatrique, les problèmes de comportement seraient très répandus et toucheraient particulièrement les enfants blessés à un jeune âge. En effet, le cerveau en plein développement pourrait s'avérer hautement vulnérable aux effets d'une atteinte cérébrale. Cependant, en ce qui concerne les formes plus légères de TCC (TCC léger; TCCL ou " commotion cérébrale "), les évidences restent mitigées. Alors que certaines études montrent peu, voire aucune manifestation comportementale du TCCL chez le jeune enfant, d'autres études révèlent des difficultés plus significatives et persistantes. L'objectif principal de la présente thèse était de caractériser les conséquences comportementales du TCCL chez l'enfant d'âge préscolaire (≤ 5 ans). La thèse est composée de trois articles empiriques. L'objectif du premier article était d'investiguer la présence de comportements internalisés et externalisés chez l'enfant six mois post-TCCL. Un deuxième objectif était d'identifier les caractéristiques préexistantes de l'enfant et de sa famille, ainsi que les variables liées à la blessure, susceptibles de prédire la présence de difficultés comportementales post-TCCL. L'échantillon comprenait 229 enfants âgés entre 18 et 60 mois, répartis en trois groupes : enfants ayant subi un TCCL (n = 86), enfants avec une blessure orthopédique (n = 62) et enfants contrôles en bonne santé (n = 81). Les résultats révèlent que les enfants d'âge préscolaire ayant subi un TCCL présentent davantage de comportements internalisés et externalisés que leurs pairs six mois après l'accident. En outre, la présence de difficultés comportementales pré-morbides, de même qu'un niveau plus élevé de détresse maternelle, prédisent davantage de difficultés comportementales six mois post-TCCL. Le deuxième article visait à caractériser les changements longitudinaux de ces comportements internalisés et externalisés observés à six mois post-TCCL. Les résultats indiquent que les difficultés comportementales observées à six mois post-TCCL persistent jusqu'à 30 mois après la blessure. Bien qu'à l'échelle du groupe, les résultats demeurent dans les limites des normes attendues pour l'âge, il existe un sous-groupe d'enfants ayant subi un TCCL qui présente des difficultés qui sont cliniquement significatives et qui persistent au long cours. Le troisième article visait à explorer l'association entre la présence d'un polymorphisme commun du gène BDNF (Val66Met), impliqué dans les mécanismes de plasticité cérébrale, et la présence de comportements internalisés et externalisés post-TCCL, au sein de cette même cohorte d'enfants d'âge préscolaire. Les résultats indiquent un effet protecteur du polymorphisme Val66Met sur les comportements internalisés observés six mois après l'accident, spécifique au groupe d'enfants ayant subi un TCCL. Les résultats issus de cette thèse permettent de mieux comprendre les conséquences comportementales du TCCL préscolaire, la trajectoire longitudinale des manifestations comportementales et la contribution de certains facteurs propres à l'enfant et à son environnement familial. Ultimement, cette thèse pourrait contribuer à préciser les orientations ministérielles concernant la prise en charge clinique du TCCL chez le jeune enfant et à mieux outiller les cliniciens œuvrant auprès de cette population vulnérable. / Pediatric traumatic brain injury (TBI) is a leading cause of long-term disability in children and adolescents worldwide. Amongst the wide array of consequences known to occur after pediatric TBI, behavioral impairments are among the most widespread and may particularly affect children who sustain injury early in the course of development (i.e., before the age of 6 years). Indeed, recent evidence suggest that the developing brain could be highly vulnerable to injury due to neurobiological and developmental particularities. When it comes to pediatric mild TBI (mTBI or "concussion"), which represents the vast majority of TBI cases in children, there is mixed evidence regarding the extent and chronicity of behavioral consequences. While some studies show little or no evidence of behavioral changes after mTBI sustained in the early years of life, others document persistent behavioral consequences. There is a paucity of studies focusing on early TBI, which likely contributes to the heterogeneity of findings. The overarching aim of this thesis was to characterize behavioral consequences of mTBI sustained in early childhood (i.e., between 18 and 60 months old). The thesis is composed of three empirical articles. The aim of the first article was to document the presence of internalizing and externalizing behavior problems six months after preschool mTBI. A second objective was to identify pre-existing child and family characteristics, as well as injury-related variables that could predict behavioral outcome. The sample consisted of 229 children recruited to one of three participant groups: mild TBI (mTBI; n = 86), orthopedic injury (OI; n = 62) and typically developing children (TDC; n = 81). The results indicate that children who sustain preschool mTBI exhibit more internalizing and externalizing problems than their peers six months post-injury. Results also show that pre-injury behavioral problems, as well as higher levels of maternal distress, predict poorer post-TBI behavioral functioning. The second article intended to characterize longitudinal changes in behavioral outcome over 30 months post-injury in the same cohort of preschoolers. Results indicate that the higher rates of internalizing and externalizing symptoms observed in the mTBI group at six months post-injury persist up to 30 months post-injury. Although at the group level, results remain within the expected age norms, there is evidence of a subgroup of children with mTBI who present clinically significant behavioral symptoms, even in the long-term. The third article aimed to explore the association between the presence of a common and naturally occurring polymorphism of the BDNF gene (Val66Met), known to be involved in neuroplasticity mechanisms, and behavioral problems after preschool mTBI. Results indicate a protective effect of the Val66Met polymorphism on internalizing symptoms observed at six months post-injury, specific to the mTBI group. Taken together, these findings further our understanding of the behavioral consequences of mTBI in early childhood, the trajectory of recovery and factors that are associated with behavioral difficulties after early TBI. Ultimately, this thesis could contribute to the development of ministerial guidelines for the clinical management of mTBI in young children and support the efforts of clinicians working with this vulnerable population.

Major depressive disorder (MDD) will soon represent the most costly and debilitating disorder in the world. Yet, a clear model of the mechanisms underlying MDD remains elusive. This lack of clarity obscures efforts to prevent and treat MDD more effectively. This dissertation seeks to advance an integrated model of the mechanisms underlying MDD across cognitive, neural, and genetic levels of analysis. Building on the empirical foundation of cognitive theories of MDD, the dissertation includes three studies that help address questions about the cognitive mechanisms underlying depression vulnerability and maintenance. Specifically, the three studies focus on identifying 1) how elaborative processing biases, including attentional biases and rumination, give rise to specific symptoms of MDD and 2) elucidating biological mechanisms that may give rise to these biases. Together, these studies help advance an integrated model of MDD that, ultimately, may help facilitate the prevention and treatment of this costly and debilitating disorder. / text

La prévalence des troubles du sommeil et de douleur chronique est élevée chez le patient ayant subi un traumatisme crânien cérébral léger (TCCL). L’interaction entre ces plaintes est suggérée chez les patients avec un TCCL mais son étiologie reste encore peu connue. Les résultats de recherche présentés dans le premier article de cette thèse suggèrent que les patients avec un TCCL qui souffrent de douleur ont une modification des ondes cérébrales durant leur sommeil, ce qui pourrait expliquer en partie comment les deux symptômes interagissent. De plus, la douleur, surtout si associée à des troubles de l’humeur, semble jouer un rôle majeur dans la persistance des symptômes post-commotionnels. Le deuxième article de cette thèse décrit une exacerbation des symptômes post-commotionnels chez le patient ayant eu un TCCL et souffrant de douleur. La persistance ou l’apparition de la douleur chronique à long terme serait prédite par le polymorphisme val66met du gène brain-derived neurotrophic factor (BDNF). Une étude subséquente, présentée dans le troisième article, nous a permis d’approfondir les bases génétiques et cellulaires du rôle du BDNF dans la persistance des symptômes post-commotionnels. Des polymorphismes fréquents dans le gène BDNF ont révélé des variantes liées au mauvais pronostic suite à un TCCL. De plus, l’analyse de cellules extraites de patients ayant subi un TCCL démontrent que l’expression de la protéine BDNF peut être modifiée chez le patient de génotype met66 et ayant subi un TCCL, lui conférant ainsi un rôle neuroprotecteur potentiel. En résumé, nous avons tenté de démontrer dans cette thèse que la douleur suite à un TCCL joue un rôle important dans les perturbations du sommeil et dans la persistance des symptômes post-commotionnels. Une prédisposition génétique pourrait contribuer à expliquer le mauvais pronostic et la chronicité des symptômes post-commotionnels suite à un TCCL. / Mild traumatic brain injury (MTBI) is a major public health concern as patients are left, amongst other symptoms, with sleep complaints and chronic pain. An interaction between these symptoms is suggested. For instance, a night of poor sleep is usually followed by hypersensitivity to pain and chronic pain always leads to sleep complaints. This interaction is suggested following an MTBI, however, data sustaining that hypothesis are still lacking. Data from the first article suggest that pain and other post-concussion symptoms are correlated with sleep-wake disturbances post-MTBI. MTBI patients with pain have more rapid electroencephalographic (EEG) waves during sleep than those without pain. This may suggest that there is an intrinsic physiological relationship between the two complaints. Moreover, pain seems to play an important role in the persistence of post-concussive symptoms. The second article of this thesis describes and details the exacerbation of post-concussive symptoms in the presence of pain following MTBI. The val66met polymorphism in the Brain-derived neurotrophic factor (BDNF) gene is an important predisposing factor for chronic pain. Lastly, a subsequent study, presented in the third article details the genetic and cellular basis of the role of BDNF in the persistence of post-concussive symptoms. Common polymorphisms in the BDNF genes were genotyped and revealed variants related to post-concussive symptoms following MTBI. Moreover, protein expression studies in lymphoblast cells of MTBI patients showed a modified expression of BDNF with the met genotype that might be neuroprotective. In summary, this thesis first shows that pain contributes to sleep-wake disturbances following MTBI and that the chronicity of post-concussive symptoms, including chronic pain, may be dependent on polymorphisms in the BDNF gene.

Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2017-10-05T12:11:04Z No. of bitstreams: 1 LUISA_AZAMBUJA_ALCALDE_DIS.pdf: 1021854 bytes, checksum: 5eb77630a0526fda862d94ab0a753c16 (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-10-05T14:47:01Z (GMT) No. of bitstreams: 1 LUISA_AZAMBUJA_ALCALDE_DIS.pdf: 1021854 bytes, checksum: 5eb77630a0526fda862d94ab0a753c16 (MD5) / Made available in DSpace on 2017-10-05T14:58:04Z (GMT). No. of bitstreams: 1 LUISA_AZAMBUJA_ALCALDE_DIS.pdf: 1021854 bytes, checksum: 5eb77630a0526fda862d94ab0a753c16 (MD5) Previous issue date: 2017-02-23 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the mammalian Central Nervous System, and plays a key role in development and physiology, as well as in pathological states. Post-mortem studies demonstrated that BDNF levels are reduced in the brains of patients affected by neurodegenerative diseases, such as Alzheimer?s disease (AD). Iron accumulation has consistently been associated to the pathogenesis of neurodegenerative diseases. In rats, neonatal iron overload induces memory deficits, and increases oxidative stress and apoptotic markers, and decreases the expression of the synaptic marker, synaptophysin. Deferiprone (DFP) is an oral iron chelator used for the treatment of systemic iron overload disorders, and has recently been tested in Parkinson?s disease patients. Here, we aimed to determine the effects of iron overload on BDNF levels and glucose metabolism, measured by 18FDG uptake using positron emission tomography. Moreover, we intended to characterize the effects of DFP on iron-induced memory deficits and BDNF levels, as well as on glucose metabolism. Rats received iron or vehicle at postnatal days 12-14 and when adults, received chronic DFP or water. Recognition memory was tested 19 days after the beginning of chelation therapy. 18FDG uptake was performed 24 h after the last day of treatment. Another subset of animals was sacrificed 24 h after the last day of treatment for BDNF measurements, and TrkB and p75 expression analysis. DFP was able to restore memory impairment and increase hippocampal BDNF levels, ameliorating iron-induced effects. The present findings support the use of DFP in clinical trials including AD patients. / O ferro ? essencial no c?rebro neonatal para o desenvolvimento neurol?gico normal e para o estabelecimento da concentra??o de ferro no c?rebro adulto, j? que a absor??o de ferro ? m?xima durante o per?odo neonatal. Acredita-se que a sobrecarga de ferro contribui para o desenvolvimento da neurodegenera??o, na exacerba??o das taxas normais de apoptose, em grande parte devido ? sua participa??o na rea??o de Fenton e ? produ??o de esp?cies reativas de oxig?nio. Estudos pr?vios em nosso laborat?rio demonstraram que o tratamento com ferro no per?odo neonatal induz altera??es significativas de mem?ria, bem como aumento em par?metros de estresse oxidativo e em n?veis de prote?nas apopt?ticas. Recentemente, tamb?m demonstramos que esse tratamento reduz os n?veis de sinaptofisina (um marcador sin?ptico) no hipocampo. O BDNF ? a neutrofina mais abundante no SNC dos mam?feros, tendo sua a??o mediada pelo receptor tirosina cinase de alta afinidade (TrKB). Atualmente, estudos tem demonstrado que o BDNF apresenta um papel cr?tico na forma??o da mem?ria de longa dura??o. Assim, o presente estudo teve dois objetivos principais. O primeiro objetivo foi verificar o envolvimento do BDNF nos d?ficits de mem?ria induzidos pelo ac?mulo de ferro, al?m de verificar se o tratamento com ferro alteraria os n?veis de BDNF e a express?o de seus receptores, TrKB e p75. Os ratos Wistar machos receberam ve?culo ou ferro carbonila (30 mg/kg) do 12? ao 14? dia p?s-natal. Na idade adulta, os animais foram tratados por 21 dias com o quelante de ferro, deferiprona (125 mg/kg/dia), e submetidos ? tarefa de reconhecimento do objeto. A an?lise da mem?ria foi realizada atrav?s do ?ndice de reconhecimento, expresso pela raz?o entre a quantidade de tempo gasto na explora??o do objeto novo sobre o tempo total gasto explorando ambos os objetos. Os n?veis prot?icos de BDNF e a express?o g?nica de seus receptores no hipocampo foram quantificados atrav?s de ELISA e PCR real time, respectivamente. O segundo objetivo foi avaliar o metabolismo glicol?tico cerebral realizado atrav?s do escaneamento no TriumphTM microPET e a capta??o de 18F-FDG utilizando o software PMOD v3.5 e Fusion Toolbox. Para este experimento, foram inclu?dos 4 grupos experimentais: os grupos que receberam ve?culo ou ferro no per?odo neonatal que foram divididos em subgrupos que receberam ve?culo ou deferiprona durante 21 dias consecutivos na idade adulta. Os ratos tratados com ferro no per?odo neonatal apresentaram uma diminui??o significativa nos n?veis de BDNF no hipocampo, sem altera??o da express?o g?nica dos receptrores TrkB e p75. A deferiprona foi capaz de reverter os d?ficits de mem?ria de reconhecimento, bem como aumentar os n?veis prot?icos de BDNF no hipocampo, melhorando os efeitos induzidos pelo tratamento com ferro no per?odo neonatal. N?o foram observadas altera??es no metabolismo da glicose cerebral nos animais tratados com ferro e/ou deferiprona. Os presentes achados fornecem embasamento para uso da deferiprona em ensaios cl?nicos, incluindo pacientes com doen?a de Alzheimer.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2017-06-12T18:00:24Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) CARLOS BORGES FILHO.pdf: 1634053 bytes, checksum: f644f69e5e2309834c31b95712982bd3 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2017-06-12T18:00:55Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) CARLOS BORGES FILHO.pdf: 1634053 bytes, checksum: f644f69e5e2309834c31b95712982bd3 (MD5) / Made available in DSpace on 2017-06-12T18:00:55Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) CARLOS BORGES FILHO.pdf: 1634053 bytes, checksum: f644f69e5e2309834c31b95712982bd3 (MD5) Previous issue date: 2016-12-30 / A depressao e uma doenca altamente incapacitante e que tem acometido um percentual crescente da populacao mundial. Ainda que varios antidepressivos estejam comercialmente disponiveis ha decadas, os efeitos colaterais destas drogas, aliados ao fato de que nem todos os pacientes respondem satisfatoriamente ao tratamento, levam a uma busca continua por novas alternativas para o tratamento ou complementacao do tratamento da depressao. Assim, expande-se cada vez mais o numero de estudos que avaliam compostos candidatos a antidepressivos. Neste contexto e que o efeito tipo-antidepressivo da crisina, um flavonoide natural abundante no maracuja do mato (Passiflora coerulea), em camundongos submetidos ao estresse cronico imprevisivel (UCS) foi demonstrado anteriormente por nosso grupo. No entanto, os fatores neuroquimicos associados a este efeito carecem de maiores investigacoes. Deste modo, o objetivo deste estudo foi avaliar os fatores neuroquimicos associados ao efeito tipo-antidepressivo do flavonoide crisina em dois modelos animais de depressao, o modelo do UCS e o modelo da bulbectomia olfatoria (OB), ambos em camundongos. No modelo do UCS foram avaliados o cortex pre-frontal (PFC) e o hipocampo (HP), enquanto no modelo da OB foi avaliado o HP. O UCS e a OB induziram um comportamento tipo-depressivo, caracterizado pela diminuicao no tempo de lambida no teste de borrifagem de sacarose e pelo aumento no tempo de imobilidade no teste de suspensao de cauda ou no teste de nado forcado. Ainda, a OB ocasionou alteracoes no teste de campo aberto, decorrentes da hiperatividade caracteristicamente induzida por este modelo. O tratamento oral com crisina (5 ou 20 mg/kg, durante 28 dias no modelo do UCS, e por 14 dias no modelo da OB), de forma semelhante a fluoxetina (10 mg/kg, controle positivo), culminou na prevencao destas alteracoes, confirmando a acao tipo-antidepressiva da crisina nos parametros comportamentais avaliados. O UCS ocasionou o aumento nos niveis plasmaticos do hormonio liberador de corticotrofina, do hormonio adrenocorticotrofico, e a atividade das caspases 3 e 9 nas estruturas cerebrais avaliadas, enquanto a OB ocasionou a reducao dos niveis hipocampais do fator neurotrofico derivado do encefalo. O UCS e a OB resultaram no aumento dos niveis de citocinas proinflamatorias nas estruturas cerebrais avaliadas, como fator de necrose tumoral-α, interferon- γ, interleucina-1β, interleucina-6, alem do aumento dos niveis de quinurenina. O UCS e a OB tambem induziram a diminuicao dos niveis de 5-hidroxitriptamina (5-HT) e o aumento da 11 atividade da enzima indoleamina-2,3-dioxigenase. O tratamento com crisina, de forma semelhante a fluoxetina, promoveu a atenuacao de todas estas alteracoes ocasionadas pelo UCS ou pela OB. Em suma, os resultados deste estudo vem a corroborar com a hipotese de que o flavonoide crisina e um alvo potencial no estudo de novas alternativas para o tratamento ou para a complementacao do tratamento da depressao. Adicionalmente, este trabalho indica a associacao das citocinas pro-inflamatorias, da via da quinurenina, do metabolismo da 5-HT, das neurotrofinas e da atividade das caspases na acao tipo-antidepressiva exercida pela crisina em camundongos expostos ao UCS ou a OB. Finalmente, o presente trabalho expoe o maracuja do mato como um importante alvo para o estudo dos produtos naturais no combate a depressao, mostrando a fundamentalidade da investigacao da funcionalidade e constituicao bioativa desta e outras plantas do bioma pampa. / Depression is a highly incapacitating disease that has affected a crescent percentage of the world population. Although various antidepressants have been commercially available for decades, the side effects of these drugs, together with the fact that not all patients respond satisfactorily to treatment, lead to continuous search for new alternatives for the treatment or supplementary treatment of depression. Thus, the number of studies evaluating compounds candidate to antidepressants expands increasingly. In this context, the antidepressant-like effect of chrysin, a natural flavonoid abundant in passion fruit bush (Passiflora coerulea), in mice subjected to unpredictable chronic stress (UCS) has been previously demonstrated by our group. However, neurochemical factors associated with this effect require further investigations. Thus, the objective of this study was to evaluate the neurochemical factors associated with the antidepressant-like effect of chrysin in two animal models of depression, the model of UCS and the model of olfactory bulbectomy (OB), both in mice. In the UCS model the prefrontal cortex (PFC) and the hippocampus (HP) were evaluated, in the OB model the HP was evaluated. The UCS and OB induced a depressive-like behavior, characterized by the decrease in the total time of grooming in the splash test and by increase on immobility time in the tail suspension test or forced swimming test. Still, OB induced changes in open field test, resulting from the hyperactivity characteristically induced by this model. The oral treatment with chrysin (5 or 20 mg/kg for 28 days in the UCS model and for 14 days in OB model), similarly to fluoxetine (10 mg/kg, positive control) resulted in the prevention of these changes, confirming the antidepressant-like action of chrysin in the behavioral parameters evaluated. The UCS led to an increase in plasma levels of corticotropin-releasing hormone, adrenocorticotropic hormone and activity of caspases 3 and 9 in the brain structures evaluated, while the OB caused a reduction of hippocampal levels of brain-derived neurotrophic factor. The UCS and OB resulted in increase of proinflammatory cytokines levels in the brain structures evaluated, such as tumor necrosis factor-α, interferon- γ, interleukin-1β, interleukin-6, and increase kynurenine levels. UCS and OB also induced the decrease in 5-hydroxytryptamine (5-HT) levels and the increase of the activity of indoleamine-2,3-dioxygenase enzyme. Treatment with chrysin, similarly to fluoxetine, 13 promoted the attenuation of all these changes caused by UCS or OB. In summary, results of this study come to corroborate the hyphotesis that the flavonoid chrysin is a potential target in the study of new alternatives for the treatment or complement treatment of depression. Additionally, this study indicates the association of pro-inflammatory cytokines, of kynurenine pathway, of 5-HT metabolism, of neurotrophins and of caspases activities in the antidepressant-like action exerted by chrysin in mice exposed to UCS or OB. Finally, this paper exposes the passion bush as an important target for the study of natural products to combat depression, showing the importance of research of functionality and bioactive constitution of this and other plants of the pampa biome.

Introdução: Perda de memória é um dos sintomas mais comuns em pacientes nos estágios iniciais da doença de Alzheimer; esses déficits são um reflexo do envolvimento da formação do hipocampo. O BDNF tem sido relacionado com a plasticidade do hipocampo. Neste sentido, as combinações de biomarcadores, como, por exemplo, a volumetria do hipocampo, pode apresentar um maior valor preditivo para diferenciar doença de Alzheimer do envelhecimento normal em pacientes com comprometimento cognitivo leve. Objetivo: A presente tese de doutorado teve como objetivo avaliar os níveis séricos do BDNF e o volume do hipocampo em pacientes com demência devido à doença de Alzheimer, Comprometimento Cognitivo Leve (CCL) e idosos saudáveis. Métodos: Para realização do estudo foram selecionados 10 idosos saudáveis, 10 CCL e 13 pacientes com demência devido à doença de Alzheimer pelos critérios NIA-AA. Todos participantes foram submetidos a uma avaliação cognitiva. Para as análises do BDNF, foi utilizado método de ELISA e para as análises de volumetria do hipocampo as imagens foram obtidas por meio de equipamento de ressonância de 1.5T e os volumes obtidos por meio do programa NeuroQuant®. Resultados: Idosos saudáveis apresentaram níveis séricos mais elevados de BDNF do que os CCL e pacientes com demência. O grupo de pacientes com demência apresentou menor volume total do hipocampo do que os idosos saudáveis e os CCL. Não houve correlação significativa do BDNF sérico com volume do hipocampo. Conclusão: Considerando nossos resultados em conjunto (baixos níveis de BDNF nos grupos CCL e demência devido à DA e menor volume do hipocampo na demência devido à AD), podemos supor que a diminuição dos níveis de BDNF ocorre antes da lesão neuronal expressa pela redução do hipocampo. / Introduction: Memory impairment is the most common symptom in patients in the early stages of Alzheimer's disease; this deficit is a reflection of the involvement of the hippocampal formation. BDNF has been linked to the hippocampal plasticity. Combinations of biomarkers, such as the hippocampal volumetry may have higher predictive value for differentiating Alzheimer's disease from normal aging in patients with mild cognitive impairment. Objective: The objective of present thesis was to evaluate serum levels of BDNF and hippocampal volume in patients with Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease, and healthy elderly participants. Method: Ten healthy elderly subjects, 10 MCI and 13 patients with dementia due to Alzheimer's Disease (NIA-AA criteria) were selected for the study. All participants were assessed cognitively. The ELISA method was used for BDNF analysis, and the analysis of hippocampal volumetric images were acquired with 1.5T magnetic resonance equipment and volumes obtained with NeuroQuant® program. Results: Healthy elderly had higher BDNF serum levels than MCI and dementia due to AD patients. The group of dementia patients had lower total hippocampal volume than MCI and healthy elderly participants. No significant correlation between serum BDNF and hippocampal volume was observed. Conclusion: Taking our results together (lower BDNF levels in MCI and dementia due to AD and smaller hippocampal volume in dementia due to AD) we can hypothesize that the decrease of BDNF may start before the establishment of neuronal injury expressed by the hippocampal reduction.

O envelhecimento da população mundial aumentou o interesse na busca pelos mecanismos fisiológicos e bioquímicos envolvidos no processo do envelhecimento saudável e por estratégias preventivas e terapêuticas de doenças relacionadas à idade. O envelhecimento cerebral alterou a atividade global de histona desacetilases (HDAC), enzima envolvida nos níveis de acetilação de histonas, marca epigenética relacionada com a expressão gênica. Nosso grupo de pesquisa demonstrou que o protocolo de exercício físico diário em esteira reduziu a atividade global da HDAC no córtex frontal imediatamente e 1 hora após a última sessão de treino. Assim, é de interesse elucidar as isoformas de HDAC envolvidas no processo de envelhecimento e no efeito do exercício físico. O exercício físico voluntário aumenta os níveis do Fator Neurotrófico Derivado do Encéfalo (BDNF) por mecanismos epigenéticos, no entanto, o impacto do exercício forçado parece ser contraditório. Nossos objetivos foram avaliar os efeitos do envelhecimento e do exercício de corrida sobre os níveis de HDAC2 e de BDNF em córtex pré-frontal de ratos Wistar. Para isso, utilizamos ratos Wistar machos com 3 e 20 meses de idade. Os animais do grupo exercitado foram submetidos ao protocolo diário de exercício físico moderado em esteira por 14 dias. No 13° dia, os animais foram submetidos à tarefa da esquiva inibitória (treino) e, no 14° dia, 30 minutos após a última sessão de exercício físico, foi realizado o teste do paradigma da esquiva inibitória. Após 30 minutos do teste na esquiva inibitória (uma hora após a última sessão de exercício), os córtices foram obtidos para os ensaios bioquímicos. Os níveis da HDAC2 foram maiores em córtices de animais envelhecidos. Ainda, foi observada uma correlação negativa entre o conteúdo da HDAC2 e o desempenho no teste de memória aversiva (esquiva inibitória). O exercício físico em esteira não alterou os níveis de HDAC2 em nenhuma das idades testadas. O envelhecimento e o exercício físico em esteira não alteraram os níveis de BDNF. Nossos dados sugerem que os altos níveis de HDAC2 estão envolvidos com o pior desempenho de animais envelhecidos na memória aversiva e que esta isoenzima não está relacionada aos efeitos epigenéticos do exercício físico em córtex pré-frontal. / Increasing attention has been paid to study the physiological and biochemical mechanisms of healthy aging process as well to seek therapeutic and protective strategies for age-related neurodegenerative diseases, since the aging population is growing. Epigenetic marks related to gene expression has been involved in aging brain process; increases in global histone desacetylase (HDAC) activity, enzyme involved with histone acetylation levels, has been found in aged brain areas. Our research group demonstrated that daily treadmill exercise protocol reduced global HDAC activity in frontal cortex immediately and 1hr after the last training session. The role of HDAC isoforms in aging process and exercise effects still needs to be elucidated. Taken that a specific HDAC isoform, HDAC2, has been involved with formation of hippocampus-dependent memory, the involvement of HDAC2 in aging process and exercise effects must be considered. Besides, it was described that voluntary exercise increases the levels of brain-derived neurotrophic factor (BDNF) through epigenetic mechanisms; while the forced exercise effects on BDNF levels seem be contradictory. Our aim was to evaluate the aging and exercise effects on HDAC2 and BDNF levels in prefrontal cortices of Wistar rats. Young adult and age male Wistar rats were submitted to a daily moderate treadmill exercise protocol (20 min/day during 14 days). The rats were assigned to sedentary and exercise groups. Single-trial step-down inhibitory avoidance (IA) conditioning was employed as an aversive memory paradigm. In the training trial (IA), rats were placed on a platform and immediately after stepping down on the grid received a footshock prior to removal from the apparatus. The test trial took place 24 hours after the training trial. Prefrontal cortices were obtained thirty minutes after inhibitory avoidance test, what was 1 hour after the last training session of exercise. HDAC2 levels were increased in cortices of aged rats. Moreover, a negative correlation was observed between HDAC2 content and aversive memory performance evaluated by inhibitory avoidance. Treadmill exercise did not alter the HDAC2 levels in any evaluated age. Aging process and treadmill exercise were unable to alter BDNF levels. Our results suggest that the age-related memory impairment may be associated with the increased HDAC2 levels.

Introdução: O hálux valgo é uma importante causa de dor e desconforto e acomete 28% dos adultos e 37% dos idosos, com predominância na população feminina. Para atingir a cura desta deformidade, faz-se necessário o tratamento cirúrgico, cuja principal razão é o tratamento da incapacidade relacionada à dor (IRD). No entanto, um ano após a cirurgia de hálux valgo, dor crônica moderada a grave persiste em 21% em repouso e 43% durante a caminhada. Esta resposta anormal faz parte dos sintomas que constitui a síndrome de sensibilização central (SSC), a qual é decorrente de um processo de neuroplasticidade mal adaptativa. Pacientes sensibilizados, não só têm uma maior propensão a desenvolver dor persistente pós-operatória como também experenciam uma dor pós-operatória mais intensa em comparação com pacientes não sensibilizados, devido à amplificação da resposta a estímulos nociceptivos e disfunção dos sistemas inibitórios. Relacionadas ao processo de alterações neuroplásticas, encontramos proteínas tais como o fator neurotrófico derivado do cérebro (BDNF). Esta neurotrofina participa do processo de LTP, mecanismo de neuroplasticidade que sustenta o processo de memória dolorosa. O aumento de BDNF incrementa a LTP, enquanto que a redução de seus níveis atenua este fenômeno. Portanto, a relação de níveis de BDNF com a severidade da doença pode confirmar a influência sistêmica desse biomarcador em estados de dor sustentada. A fim de alterar a neuroplasticidade mal adaptativa induzida pela dor a longo prazo, a estimulação transcraniana por corrente contínua (ETCC), uma técnica não invasiva, que visa à modulação do sistema nervoso central para controle da dor, pode se tornar uma opção terapêutica. No entanto, ainda não foi explorado o efeito da ETCC aplicada no período pré-operatório com intuito de melhorar o controle da dor pós-operatória de pacientes sensibilizadas e melhorar a reabilitação pós-operatória dessas pacientes. Neste estudo optou-se pelo uso da ETCC pelo seu potencial de contra regular as alterações ETCC pré-operatória comparada ao ETCC-sham no controle da dor e reabilitação em pacientes com artralgia da 1ªAMF submetidas a tratamento cirúrgico de hálux valgo. Método: Ensaio clínico, randomizado, duplo-cego, em paralelo, controlado com sham que incluiu 40 pacientes do sexo feminino, entre 18 e 70 anos, candidatas a tratamento cirúrgico de hálux valgo sob técnica combinada de Chevron e Akin por artralgia da 1ªAMF. As pacientes foram randomizadas e divididas em dois grupos que receberam duas sessões de 20 minutos de ETCC-ativa(a) ou ETCC-sham(s) no período pré-operatório. A estimulação foi feita por corrente contínua de 2mA através do eletrodo anodal sobre o córtex motor primário (M1) e o catodal sobre a área supraorbital contralateral. Os desfechos avaliados foram: escores de dor na EAV(0-10), consumo analgésico, IRD avaliada pela B-PCP:S, função do sistema modulador descendente da dor, avaliada pelo teste CPM e os níveis séricos e liquóricos de BDNF. Resultados: O grupo ETCC-a apresentou escores mais baixos na escala Análogo Visual de Dor [EAV(0-10)] em repouso e durante a caminhada (P <0,001). Em repouso, a diferença entre os dois grupos foi de 2,13cm (95% IC = 1,59 a 2,68), enquanto durante a caminhada foi de 1,67cm (IC 95% = 1,05 a 2,28). O grupo ETCC-a, quando comparado ao grupo ETCC-s mostrou menor necessidade de doses analgésicas diárias com média de 1,37 (0,63) contra 1,81 (0,64) doses respectivamente (P <0,001). A ETCC ativa também obteve maior melhora da IRD que a ETCC sham, conforme demostrado pela maior redução na Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (diferença média de 9,41 pontos, IC95% = 0,63 a 18,21) e ainda, aumentou a função do sistema modulador descendente da dor durante o teste da modulação condicionada de dor (CPM) com um tamanho de efeito médio. O aumento da função desse sistema representa a reversão das alterações neuroplásticas mal adaptativas promovidas pela dor crônica. Conclusão: Duas sessões de ETCC anódica aplicadas sobre M1 no pré-operatório melhorou a dor pós-operatória, como demonstrado pela redução dos escores de dor, consumo de analgésicos e IRD. Além disso, sugere-se que os efeitos da ETCC pré-operatória nestes desfechos envolvem a melhora da função dos sistemas moduladores descendentes da dor e mecanismos de neuroplasticidade conforme mensurados pelo BDNF. / Introduction: Hallux valgus, is an important cause of feet pain and discomfort and affects 28% of adults and 37% of elderly, predominantly in female population. To achieve the deformity heal, surgical treatment is needed, which main goal is to treat incapacity related to pain (IRP). However, one year after hallux valgus surgical treatment, moderate to severe chronic pain persists in 21% during rest and 43% during walking. This abnormal response is part of the symptoms that constitute central sensitization syndrome (CSS), which is due to a maladaptive neuroplasticity process. Sensitized patients, not only are more likely to develop postoperative persistent pain, but also experience more intense postoperative pain comparing to non-sensitized patients, due to the amplification of nociceptive inputs and inhibitory systems disfunction. Related to neuroplasticy process, proteins such as brain neurotrophic factor (BDNF) are found. This neurotrophin participates in the LTP process, a mechanism of neuroplasticity that sustains the process of pain memory. The increase of BDNF increases the LTP, while the reduction of its levels attenuates this phenomenon. Therefore, the relationship of BDNF levels with disease severity may confirm the systemic influence of this biomarker on sustained pain states. In order to alter long-term pain-induced maladaptive neuroplasticity, transcranial direct current stimulation (tDCS), a non-invasive technique, which aims for the central nervous system modulation for pain control, may become a therapeutic option for postoperative pain. However, the effect of tDCS applied in the preoperative period has not been explored yet with the intent of improving the postoperative pain control in sensitized patients, neither in postoperative rehabilitation. In this study, it was chosen to use tDCS due to its potential to counter-regulate the maladaptive neuroplastic alterations associated to chronic pain. Objective: to evaluate the effect of preoperative tDCS compared to tDCS-sham in the pain control and in the rehabilitation of patients with arthralgia of the first metatarsalfalangeal articulation submitted to hallux valgus surgical correction. Method: it is a randomized, double-blinded, placebo-sham controlled clinical trial, which includes 40 female patients, between 18 and 70 years old, candidates to hallux valgus surgical treatment by combined Chevron + Akin osteotomy due to arthralgia of the first metatarsalfalangeal articulation. The patients were randomized and divided into two groups that were treated with two tDCS or tDCS-sham sessions of 20 minutes each in preoperative period. The stimulation was done by 2mA continuous current through the anodal electrode on the primary motor cortex (M1) and the catodal on the contralateral supraorbital area. The outcomes were: VAS(0-10) scores, analgesic consumption, DRP assessed by the B-PCP: S, the function of the descending pain modulator system, assessed by the CPM test and the serum and CSF levels of BDNF. Results: a-tDCS group showed lower scores on Visual Analogue Scale [VAS(0-10)] at rest and during walking (P<0.001). At rest, the difference between both groups was 2.13cm (95%CI=1.59 to 2.68) while during walking was 1.67cm (95%CI=1.05 to 2.28). The a-tDCS group, when compared to s-tDCS, showed reduced need of daily analgesic intake from 1.37 (0.63) to 1.81 (0.64) mean doses, respectively (P<0.001). Active tDCS improved the DRP, as demonstrated by a greater reduction in the Brazilian Profile of Chronic Pain: Screen (B-PCP:S) (mean difference of 9.41 points, 95%CI=0.63 to 18.21) and also increased the function of descending pain modulatory system (DPMS) during conditioned pain modulation (CPM-task), with a medium size effect. The increased function of this system represents the reversal of maladaptive neuroplastic changes promoted by chronic pain. Conclusion: Two preoperative anodic tDCS sessions applied over M1 improved postoperative pain, as demonstrated by reduction in the pain scores, analgesic consumption and DRP. In addition, these results suggest that the effects of preoperative tDCS on these outcomes involved improving the function of pain modulation systems and neuroplasticity mechanisms as measured by BDNF.

As leucemias correspondem a 30% dos tumores pediátricos, e constituem as neoplasias mais frequentes em indivíduos com menos de 15 anos. Apesar da elevada taxa de cura, frequentemente a ela está associada resistência à quimioterapia e efeitos colaterais tardios. Por isso, novas estratégias de tratamento, diagnóstico e prognóstico são necessárias. O fator neurotrófico derivado do cérebro (BDNF) e seus receptores de quinase relacionados à tropomiosina (tropomyosin related kinase, ou Trk) estão envolvidos com muitos processos na medula óssea (MO). Entretanto, o papel do BDNF em leucemias agudas (LA) pediátricas ainda não é bem conhecido. O objetivo desse estudo foi analisar os níveis de BDNF em amostras de MO ou sangue periférico (SP) de crianças com LA, e iniciar a caracterização dos efeitos de agonistas e antagonistas de neurotrofinas sobre culturas primárias de leucemias linfóides agudas em diferentes momentos terapêuticos Foram coletadas amostras de MO ou SP de crianças e adolescentes com leucemia linfóide aguda (LLA), crianças e adolescentes com leucemia mielóide aguda (LMA), e indivíduos saudáveis (IS) da mesma faixa etária. Para análise dos níveis séricos de BDNF utilizou-se kit de imuno-ensaio enzimático tipo sanduíche. Quando comparados aos IS os níveis de BDNF de pacientes com LA, ao diagnóstico, foram significativamente menores. Resultados similares foram observados nos pacientes durante indução, consolidação, diagnóstico e tratamento de recidiva. Da mesma forma, os níveis de BDNF foram inferiores em pacientes que receberam transfusão de plaquetas e, ao diagnóstico naqueles pacientes que foram a óbito. Para a caracterização dos efeitos de agonistas e antagonistas de neurotrofinas em cultura de células, amostras de pacientes ao momento do diagnóstico e no momento de indução do tratamento foram utilizadas. Os linfócitos foram extraídos e, após plaqueamento, as células foram tratadas com BDNF (Sigma, B3795), NGF (Sigma, SRP3015) e K252a (Sigma, 05288) por 72 horas. A viabilidade foi avaliada pelo método de exclusão por azul de Tripan. Devido às dificuldades no cultivo das células, esses dados ainda estão em análise. / Leukemias account for 30% of pediatric tumors and are the most frequent cancers in people under 15 years. Despite the high cure rate, often it is associated with resistance to chemotherapy and late side effects. Therefore, new strategies for treatment, diagnosis and prognosis are necessary. The brain-derived neurotrophic factor (BDNF) and their kinase receptor related tropomyosin (tropomyosin related kinase, and Trk) are involved in many processes in bone marrow (BM), however, the role of BDNF in acute leukemias (AL) pediatric it is not well known. The aim of this study was to analyze the BDNF levels in BM samples or peripheral blood (PB) of children with AL, and start the characterization of the effects of agonists and antagonists on neurotrophin primary cultures of acute lymphoblastic leukemias in different therapeutic moments. BM or PB samples were collected from children and adolescents with acute lymphoblastic leukemia (ALL), children and adolescents with acute myeloid leukemia (AML), and healthy individuals (HI) of the same age. For analysis of serum levels of BDNF was used sandwich enzyme immunoassay kit. When compared to HI, BDNF levels in patients with AL at diagnosis were significantly lower. Similar results were observed in patients during induction, consolidation, diagnosis and treatment of relapse. Similarly, BDNF levels were lower in patients receiving platelet transfusion and at diagnosis in patients that died. To characterize the effects of agonists and antagonists for neurotrophin in cell culture, samples of patients at diagnosis and at the time of induction treatment were used. Lymphocytes were extracted and, after plating, cells were treated with BDNF (Sigma B3795), NGF (Sigma, SRP3015) and K252a (Sigma, 05288) for 72 hours. Viability was assessed by exclusion of trypan blue method. Due to difficulties in cell culture, these data are still under analysis.