Background: A compilation of high quality systematic reviews (SRs) on lifestyle factors associated with adult glioma and meningioma was developed. Methods and Materials: Phase 1 consisted of a systematic overview of existing SRs. For Phase 2, high quality SRs were incorporated in an update. Moderate or low quality SRs which had not been considered in a high quality review were eligible for a de-novo synthesis. Results: Phase 1 resulted in seven moderate to low quality reviews. From this, in Phase 2, smoking, mobile phone and hair dye use were subjected to de-novo reviews. For smoking, it was suggestive that past smokers had an increased risk. For mobile phone use, there was no overall association, however it was suggestive that ipsilateral and high cumulative call time were associated with slight increased risk. No association was observed for personal hair dye use. Conclusions: Despite these null associations, rigorous SR methods were used providing confidence in conveying these results.

Meningioma and glioma are the most common primary brain tumors, but their etiologies are largely unknown. Although meningioma is usually benign, their intracranial location can lead to lethal consequences, and despite progress in surgery, radiotherapy, and chemotherapy the prognosis for patients with glioma remains poor. The only well-established environmental risk factor for meningioma and glioma is ionizing radiation. Evidence for inherited predisposition to meningioma and glioma is provided by a number of rare inherited syndromes where collectively these diseases account for only a small proportion of the twofold increased risk of brain tumors seen in first-degree relatives for meningioma and glioma patients. It is very possible that much of the excess familial risk is a consequence of co-inheritance of multiple low-risk genetic variations. With this in mind, the aims of the studies in this thesis were to discover genetic risk variants influencing the probability of acquiring the disease and to identify the association between risk variants on the tumor phenotype. To identify genetic variants influencing meningioma risk, a comprehensive tagging of the selected genes in a case-control study was performed. We identified nine risk variants in EGF, ERBB2, and LRIG2 genes. However, these findings could not be confirmed in another larger independent dataset. In addition, the study identified a correlation between LRIG2 protein expression and ER status when analyzed with different parameters. In a separate study with a larger sample of meningioma patients, the same correlation between LRIG2 and ER status was observed. To explore the potential association between reported germline risk variants and somatic genetic events, matched tumor and blood samples from glioma patients were analyzed by SNP array. The results identified correlations between EGFR gene variants and somatic aberrations within the EGFR locus and CDKN2A/B locus. To further study the relationship between germline risk variants and tumor phenotype, the same patient material was used and analyzed by three different techniques: SNP array, IHC, and FISH. The results revealed EGFR risk variants effecting copy number variation of the EGFR gene and the expression of the IDH1 and p53. Further comparison between different techniques such as SNP array and FISH analysis revealed the difficulty in achieving consistent results with different techniques. To summarize, the glioma studies show a link between genotype and phenotype where genetic risk variants in the EGFR gene were found to be associated with specific somatic aberrations. These associations are biologically interesting because EGFR is involved in multiple cellular processes. Additional studies of the direct functional role of these observations need to be conducted to elucidate the molecular mechanisms underlying the identified association between germline gene variants and somatic aberrations. For the meningioma studies, no significant risk variants influencing the disease were found but a correlation between LRIG2 and ER status was observed. This result suggests a potential role for the LRIG protein in the pathogenesis of meningioma, but more studies are needed to confirm this hypothesizes. / <p>Cancer research foundation in northern Sweden and Lions cancer research foundation at Umeå university</p>

<p>Glioblastoma (GBM) represents the most common and lethal brain tumor in adults, with glioma initiating cells (GICs) implicated to play a critical role in its progression and recurrence. However, the molecular mechanisms underlying the distinct function of GICs and non-GICs remain largely unknown. Elucidating distinct molecular features of GICs will pave the foundation for GIC directed therapies for GBM treatment. </p><p>We first demonstrated that GICs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6Ra) and glycoprotein 130 (gp130). Targeting IL6Ra; or IL6 ligand expression in GICs using short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Block IL6 signaling in GICs attenuates Stat3 activation, and small molecule inhibitors of STAT3 potently induce GIC apoptosis. Targeting IL6Ra; or IL6 expression in GICs increases the survival of mice bearing intracranial human glioma xenografts. The promising application of anti-IL6 therapies is demonstrated by decreased subcutaneous tumor growth of human GIC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GIC growth and survival, and that targeting IL6 may offer benefit for glioma patients.</p><p>MicroRNAs (miRNAs) are a class of non-coding small RNA molecules which negatively regulate gene expression and are deregulated in many types of cancer. Through a candidate-based screen, we identified microRNA-33a as a master determinant whose expression controls the functional differences between GIC and non-GICs. Antagonizing miR-33a function in GICs led to reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs rendered them to display features associated with GICs. Mechanistically, miR-33a acts to confer the biological property of GICs via enhancing the activities of cAMP/PKA pathway and Notch signaling by targeting negative regulators of these two pathways. Together these findings reveal a miR-33a-centered signaling network that dictates the identity/activity of GICs and consequently serves as a therapeutic target for the treatment of GBM.</p><p>In summary, this doctoral thesis reveals two novel molecular events that characterize the distinct feature of GICs and develops preclinical strategies for the therapeutic application of GBM.</p> / Dissertation

Gliomas are common primary brain tumours that occur as low-grade (LGG) and high-grade gliomas (HGG). Typically occurring in younger adults, LGG has an indolent course with a median survival of 5-10 years, but carries an inherent potential for transforming into HGG. The thesis focused on LGG in adults, with the aim of identifying prognostic biomarkers for LGG. Paper I. Epileptic seizures are common symptoms in LGG. In a retrospective study, the correlation between 11C-methionine (MET) uptake, measured by Positron Emission Tomography (PET), and seizure activity was assessed in 101 patients with LGG. Although there was no correlation between MET uptake and seizure activity, survival was longer in patients who were seizure-free before surgery. Paper II. This finding prompted the search for common genetic pathways for both tumour and seizure development and a review of genetic polymorphisms in focal epilepsy and glioma risk. Cell cycle and immune response genes affecting both glioma and seizure risk were identified, and genes involved in synaptic transmission presented potential candidates for future studies. Paper III. The transcription factor PROX1 plays a pivotal role in normal development and carcinogenesis of various organs. The prognostic value of PROX1, together with established clinical and molecular prognostic factors for survival, was retrospectively assessed in 116 patients with LGG. High PROX1 expression in the tumour was associated with shorter survival. Paper IV. DNA repair enzymes, such as ERCC6, are crucial for maintaining genomic stability in glioma response to radiotherapy. An association between the polymorphism rs4253079, mapped to ERCC6, and longer survival in patients with LGG and HGG was identified. Paper V. As LGG typically presented as non-contrast enhancing tumours on morphological MRI (magnetic resonance imaging), the value of combined MET PET with physiological MRI for preoperative diagnosis was assessed in a prospective study of 32 patients with suspected LGG. Representative tumour areas were identified through a combination of perfusion-MRI with MET PET, which can be used as a baseline investigation for follow-up over time. Conclusions: The parameters seizure-freedom before surgery, the polymorphism rs4253079 in ERCC6 and low PROX1 expression in the tumor were identified as favorable prognostic biomarkers.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Feb. 9, 2009). Includes bibliographical references.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed on June 24, 2009). Includes bibliographical references.

Une radiothérapie efficace nécessite un dépôt de dose localisé à la tumeur, et donc un contraste entre le tissu tumoral et les tissus sains environnants. Une irradiation de basse énergie monochromatique au synchrotron d'une tumeur chargée en éléments lourds permet de maximiser l'interaction photoélectrique dans la tumeur et d'épargner les tissus sains, car les photoélectrons et les électrons Auger produits ont un TEL très élevé et déposent leur énergie autour des éléments lourds, augmentant fortement le dépôt de dose. Ils peuvent induire des dommages à l'ADN (cassures double brin) fortement létaux. Un autre phénomène permet également de promouvoir l'émission d'électrons Auger et d'augmenter ainsi la dose, l'effet Mössbauer. Cette interaction résonante et sans recul spécifique à certains isotopes dont le 57Fe présente une section efficace 450 fois plus importante que celle de l'effet photoélectrique. Ce travail de doctorat a évalué l'utilisation in vitro de nanoparticules de magnétite combinées à ces deux effets physiques. Les nanoparticules présentent une internalisation et une distribution dans les cellules F98 qui sont très propices à la radiosensibilisation : de grandes concentrations proches du noyau des cellules, et peu de toxicité ont été obtenues. Ceci a permis d'obtenir par photoactivation des NPFe un facteur d'augmentation de 3 ce qui est considérable. Ce travail multidisciplinaire rassemble des expériences de physique, de biologie et de chimie, pour évaluer les applications de nanoparticules de fer à la radiothérapie. / An efficient radiotherapy needs a localized dose to the tumour, which means a high contrast between tumorous and healthy tissues. A synchrotron low energy monochromatic irradiation of a tumour charged in high-Z elements allows maximizing photoelectric interactions in the tumour and spare the healthy tissues. Photoelectrons and high LET Auger electrons thus produced deposit their energy locally, enhancing radiation dose to tumor cells. Another interaction allows to enhance the dose by Auger electrons: the Mössbauer effect. This resonant and recoilless interaction specific to some isotopes like 57Fe has a cross section 450 times bigger than photoelectric effect. This thesis evaluates the in vitro use of magnetite nanoparticles combined with those 2 types of interactions. The nanoparticles evaluated present a high internalisation and a perinuclear distribution inside F98 cells. A dose-enhancement factor of 3 was obtained by photo activation of the iron Nps, this represents a huge increase. This multidisciplinary work encompasses experiments in chemistry, physics and biology in order to evaluate the applications of magnetite nanoparticles to radiotherapy.

Les gliomes de haut-grades sont des les tumeurs primitives les plus fréquentes du système nerveux central. Le traitement de cette pathologie associe chirurgie, radiothérapie et chimiothérapie. Les principales faiblesses de ces traitements sont le caractère infiltrant de la tumeur au sein d’un parenchyme hautement fonctionnel, l’existence de la barrière hémato-encéphalique limitant le passage trans-vasculaire de la chimiothérapie et la radiorésistance naturelle des cellules gliomateuses.Parmi les stratégies proposées pour outre-passer cette barrière hémato-encéphalique, une injection directe au sein du parenchyme a été évoquée. Afin d’optimiser cette délivrance le concept d’infusion convective a été développé, il s’agit d’une injection intra-parenchymateuse à un débit lent et contrôlé.Le bevacizumab est un anticorps dirigé contre le VEGF-A, un des principaux facteurs angiogéniques. Le but de ce traitement est de lutter contre l’ angiogénèse et de freiner la croissance tumorale.Dans un premier temps, la pharmacocinétique d’une injection intracérébrale de bevacizumab a été étudiée en comparaison avec une administration systémique plus classique. Les résultats permettent de mettre en évidence une concentration locale équivalente avec des concentrations systémiques beaucoup plus faibles avec une injection intra-tumorale. Un point important de cette étude est que la concentration dans l’hémisphère controlatéral à l’injection est aussi importante que lors d’une injection systémique.Puis l’efficacité d’une injection intratumorale de bevacizumab a été comparée à un traitement systémique sur un modèle de gliome chez la souris. L’efficacité du traitement est claire sur la survie de l’animal avec un avantage pour une injection intratumorale par rapport à une injection systémique. D’un point de vue microscopique cet avantage de survie peut être corrélé à une angiogénèse et une prolifération tumorale moins importante an cas d’injection directe au sein de la tumeur.Contrairement aux études pré-cliniques chez les rongeurs, les principaux essais cliniques n’ont pas permis de mettre en évidence un avantage d’une injection intra-tumorale directe. Principalement du à une mauvaise délivrance liée à des fuites et des reflux. Une des limites du modèle petit animal est l’absence de sillon cortical, vecteur de fuite. Le développement d’un modèle de gliome anatomiquement pertinent permettrait de simuler au mieux ces fuites et simultanément la mise au point de technologies de délivrance implantable à l’échelle humaine. Nous avons donc développé le premier modèle de gliome chez le porc. L’immunotolérance a été induite par un traitement par ciclosporine, des cellules de gliomes humains U87 et G6 ont été implantés, permettant se développer des tumeurs.Afin de dépister une mauvaise délivrance et anticiper les fuites ou les reflux, nous avons étudié les profils de pression le long de la ligne d’injection corrélés à l’existence de fuites ou de reflux. Nous avons pu identifier un profil pressionnel typique d’une injection de qualité. Les injections ne répondant pas à ces critères ont systématiquement conduits à des fuites ou reflux.L’étape suivante a été l’injection au sein d’une tumeur chez des porcs grâce à un système innovant implanté. Cette injection a été possible sans complication infectieuse avec une bonne tolérance locale et neurologique.La dernière étape de ce travail est l’étude anatomique de la diffusion d’un colorant injecté par une technique d’infusion convective. Cette étude s’intéressait notamment à la diffusion depuis la corona-radiata vers les différentes voies de substance blanche. La diffusion est anisotrope le long des fibres de substance blanche cependant la diffusion suit des voies différentes en fonction de la position du cathéter par rapport à elle. L’injection semble ouvrir des voies d’impédances rhéologiques faibles préférentielles nécessitant une adaptation anatomique aux voies qui seront la cible du traitement. / High grade gliomas are the most frequent primitive central nervous system tumor. The standard treatment is an association of surgery, radiotherapy and chemotherapy. The mains issues with these treatments are the infiltrative properties of the tumour in a highly functional parenchyma, the blood-brain barrier limiting the transvascular transport of chemotherapy and the inherent radioresistance of glioma cells.Upon different strategy to overpass the blood-brain barrier, a direct injection in the brain was advocated. In order to maximize this delivery, the concept of convection enhanced delivery was developed; it consists in a direct injection in the parenchyma with a low flow-rate.Bevacizumab is an anti-VEGF A antibody, VEGF is one of the most important angiogenic factors. The goal of this treatment is to inhibit the angiogenesis and slow down the tumor growth.We propose to study the use of this antibody in a direct intra-cerebral infusion.First, we focalize on the pharmacokinetic properties of an intratumoral injection by convection –enhanced delivery compared to a systemic administration. This shows an equivalent intratumoral concentration with systemic concentrations significantly lower with the intra-tumoral injection. An important result is the similar concentration in the controlateral hemisphere with the two routes of infusion. Convection-enhanced delivery is suitable to carry far from the infusion site high molecular weight proteins. An intra-tumoral bevacizumab may theoretically provide similar efficiency with less systemic side-effect.Then, the efficiency of an intra-tumoral infusion of bevacizumab is compared to a systemic injection on a mouse glioma model. In terms of survival the intra-tumoral treatment is significantly more efficient with an important decrease of angiogenesis and tumoral proliferation.If convection-enhanced delivery rodent study were promising, clinical trials failed to show any efficiency of intra-tumoral injection mainly due to inadequate delivery secondary to backflows and leakages. One of the limits of the rodent model is the absence of cortical sulci, main leakage provider. The development of a model anatomically relevant could simulate real conditions of injection and develop implantable device of injection in realistic conditions. We have developed the first induced model of glioma in a large animal. We choose the pig for the similarity of its brain anatomy and its size. The animals have been treated with ciclosporin to induce an immunosuppression, human glioma cells have been implanted, leading to the development of brain tumor.We have studied the pressure on the infusion line and correlate it to backflow and leakage. We have identified a pattern of pressure for successful infusion. Different pressure pattern have systematically led to backflow or leakage. These pressures criteria could permit to us an early detection of inadequate infusion to replace the catheter and avoid the failure of precedent clinical trials.Next step have been the intra-tumoral injection via an implanted device on pig glioma model. No infectious complication has been related with a good local and neurologic tolerance. The injections have led to a relevant diffusion through the tumor with a rapid flow to the periphery due to the interstitial pressure gradient between the tumor and the periphery.Last step of this work have been the anatomical study of a dye distribution by convection-enhanced delivery in a human encephalon. Indeed if pig brain is similar to human brain, human white matter structure is unique. This work is focalized on the diffusion from the corona-radiata to the main white matter tracts. The distribution is anisotropic following white matter but the diffusion is different depending on the position of the catheter. The infusion seems to open low rheological impedance paths the position of the catheter have to be adapted to the white matter tract to target.

Gliomas constituem um grupo heterogêneo de tumores cerebrais. Eles podem ser divididos em duas principais categorias: astrocíticos e oligodendrogliais. Os astrocíticos, objetos deste estudo, são classificados patologicamente em quatro subtipos baseado na presença ou ausência de atipia nuclear, mitose, neovascularização e necrose. Esta classificação é útil para definir tratamento e prognóstico. A origem glial é comumente confirmada pela detecção imunoistoquímica para GFAP. Neste trabalho nós investigamos o imunoconteúdo das proteínas marcadoras astrocíticas GFAP e S100B por ELISA e a atividade da enzima glutamina sintetase (GS) em tumores gliais e tecidos peritumorais de sete pacientes submetidos à ressecção cirúrgica. Os resultados demonstram elevados níveis de S100B em tecidos peritumorais não correlacionados com o grau de malignidade do tumor. Esta elevação poderia contribuir para manifestações convulsivas observadas em alguns pacientes. Em contraste com os dados obtidos pela imunoistoquímica para filamentos gliais, encontrou-se uma aparente correlação positiva entre o conteúdo de GFAP e o grau de malignidade do glioma. É possível que este aumento no conteúdo de GFAP seja referente a GFAP total (frações solúvel e insolúvel), em contraste com o conteúdo insolúvel (fibrilar e granular) detectado pela imunoistoquímica. A alta taxa GFAP/S100B (GFAP elevada/S100B reduzida) está de acordo com a sua elevada atividade mitótica, que pela sua vez poderia ser inibida pela S100B. Além disso, houve uma correlação positiva entre a atividade da GS e o grau de malignidade do tumor.

O diabetes mellitus é uma doença metabólica caracterizada por níveis elevados de glicose no jejum e está associada com a perda da função cognitiva e um maior risco de desenvolvimento de doenças neurodegenerativas, tais como a Doença de Alzheimer (DA). As complicações do diabetes estão relacionadas com a hiperglicemia, níveis elevados de compostos reativos, como o metilglioxal (MG) e a formação de produtos finais de glicação avançada (do inglês Avanced Glycation End Products - AGEs). Os AGEs e o MG - um aldeído reativo envolvido no estresse dicarbonil e na formação de AGEs – encontram-se elevados em pacientes com diabetes e DA e têm sido sugeridos como mediadores do declínio cognitivo observado nessas patologias. Estudos indicaram que os astrócitos possuem o sistema glioxalase mais efetivo que os neurônios e, portanto, podem proteger os neurônios do estresse dicarbonil. Entretanto, as reações de glicação estão associadas com o prejuízo no funcionamento dos astrócitos, que, desta forma, comprometem a atividade neuronal. Tendo em vista que as reações de glicação estão exacerbadas no diabetes e em doenças neurodegenerativas sugere-se que nestas situações o dano neuronal seja ainda maior. Este trabalho teve como objetivo avaliar a suscetibilidade ao dano induzido pelo MG em culturas de astrócitos e de glioma C6 e examinar o efeito da alta concentração de glicose, do MG e da carboxietil-lisina (CEL), um AGE derivado da reação do MG com a lisina, em parâmetros oxidativos, metabólicos e específicos de astrócitos em fatias de hipocampo in vitro. Além disso, verificar se a administração intracerebroventricular (ICV) de MG causa alterações comportamentais, relacionadas com declínio cognitivo e ansiedade, e alterações bioquímicas em hipocampo, córtex cerebral e líquido cefalorraquidiano (LCR) ex vivo. Em culturas de células observou-se uma alta eficiência do sistema glioxalase em astrócitos em comparação com células C6. O conteúdo de glutationa diminuiu a partir de 1 hora após a exposição ao MG apenas em C6. A captação de glutamato reduziu em astrócitos e aumentou em C6, sendo que este efeito estava relacionado com reações de glicação, mas não com a expressão de transportadores de glutamato analisados. A formação de espécies reativas, a secreção de S100B e o conteúdo da proteína glial fibrilar ácida (GFAP) não foram modificados pelo tratamento com MG nas células estudadas. Em fatias de hipocampo (in vitro) verificou-se que a glicose, o MG e a CEL não alteraram a formação de espécies reativas, a captação de glicose e a atividade da glutamina sintetase. No entanto, a captação de glutamato e a secreção de S100B diminuiram após o tratamento com MG e CEL. Estas mudanças não foram mediadas pela ativação de RAGE e por reações de glicação. A partir do estudo in vivo verificou-se que o MG não causou deficiência nos processos de aprendizagem e memória investigados pelas tarefas de habituação, labirinto em Y e reconhecimento de objetos e não alterou a atividade locomotora dos animais. Contudo, o aumento agudo dos níveis exógenos de MG diminuiu o comportamento do tipo ansiedade, observado através do teste de campo aberto. Em relação às análises ex vivo, o MG induziu alterações persistentes relacionados com a atividade da glioxalase 1, conteúdo de AGEs e captação de glutamato no hipocampo. A formação de espécies reativas, o conteúdo de glutationa, o conteúdo tecidual de GFAP e S100B e a atividade da glutamina sintetase não foram alterados com a administração ICV de MG. É possível concluir que a exposição aguda, in vitro, de fatias de hipocampo ao MG e CEL, mas não à glicose, foi capaz de induzir efeitos semelhantes em fatias de hipocampo, sugerindo que a alta concentração de glicose é tóxica principalmente por elevar a concentração de compostos glicantes, como o MG, e gerar ligações cruzadas com proteínas. O MG foi capaz de induzir prejuízo na captação de glutamato em culturas de astrócitos e fatias de hipocampo, indicando que o MG gera alterações na homestase cerebral através do comprometimento da remoção do glutamato da fenda sináptica, deste modo, contribuindo com as alterações neurológicas relacionadas com o diabetes mellitus. Em suma, as concentrações exógenas de MG e o tempo de exposição a elevadas concentrações deste composto determinam as diferentes características que podem ser observadas em pacientes diabéticos. / Diabetes mellitus is a metabolic disease characterized by high fasting-glucose levels and is associated with loss of cognitive function and a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease (AD). Diabetic complications have been associated with hyperglycemia, high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation end products (AGEs) formation. AGEs and MG - a reactive aldehyde, involved in dicarbonyl stress and AGEs formation - are elevated in diabetes and AD and have been suggested as mediators of cognitive decline observed in these pathologies. Astrocytes are impaired to glycation processes, although, they have an improved glyoxalase system compared to neurons that protect them from dicarbonyl stress, suggesting that damage to neuronal functions could be increased under diabetes and neurodegenerative diseases. This study aimed to evaluate the susceptibility of astrocytes and C6 glioma cells cultures to MG damage and to examine the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in hippocampal slices in vitro. Furthermore, verify if intracerebroventricular (ICV) administration of MG cause behavioral changes, related to cognitive decline and anxiety, and biochemical alterations in the hippocampus, cerebral cortex and cerebrospinal fluid ex vivo. Since our cultures studies we observed a high efficiency of the glyoxalase system in astrocytes compared to C6 cells. The content of glutathione decreased from 1 hour after MG exposure only in C6 cells. Glutamate uptake was decreased in astrocytes and increased in C6 cells and this effect is related to glycation processes, but not to glutamate transporters expression. The reactive species formation, S100B secretion and glial fibrillary acidic protein (GFAP) content were not modified by MG treatment in either culture studied. With hippocampal slices inbucation (in vitro) it was found that glucose, MG and CEL did not alter reactive species formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions did not mediate these changes. From in vivo research it was found that MG did not cause impairment in learning-memory processes investigated by habituation, Y-maze and object recognition tasks and did not alter locomotion behavior of animals. However, the acute increase of MG exogenous levels reduced anxiety-related behavior evaluated in the open field test. Ex vivo findings support that MG induced persistent alterations related to glyoxalase 1 activity, AGEs content and glutamate uptake in hippocampus. The reactive species formation, glutathione content, GFAP and S100B content, as well as glutamine synthetase activity were not altered by MG ICV administration. It is possible conclude that acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices in vitro, suggesting that conditions of high glucose concentrations are primarily toxic by elevate the rates of these glycation compounds, as MG, and generate protein cross-links. MG-induced astrocyte glutamate uptake impairment was seen in astrocyte cultures and hippocampal slices, indicating that MG produces changes in brain homeostasis by the impairment of glutamate removal of the synaptic cleft, thus contributing to neurological changes related to diabetes mellitus. The exogenous concentrations of MG and the time of exposure to high concentrations of this compound determine the different features that can be seen in diabetic patients.