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Background: Folate and cobalamin are essential cofactors for homocysteine (HCY) metabolism. Hyperhomocysteinemia, a multifactorial condition, may reflect B vitamin deficiency and is associated with increased risk of cardiovascular disease, thrombosis, and neurodegenerative and chronic gastrointestinal diseases in humans. Hyperhomocysteinemia has been reported in Greyhounds with suspected chronic enteropathy. Objectives: To evaluate the frequencies of and the association between hypofolatemia and hyperhomocysteinemia in Greyhounds. Animals: Data and serum samples from 559 Greyhounds. Methods: Nested case-control study. The frequency of hypofolatemia in Greyhounds was determined by a laboratory database search. The relationship between hyperhomocysteinemia (measured by gas chromatography-mass spectrometry) and hypocobalaminemia and hypofolatemia was evaluated, and its frequency compared between healthy Greyhounds and Greyhounds with thrombosis or chronic diarrhea. Results: Hypofolatemia was identified in 172 of 423 (41%) Greyhounds and was more common in hypo- than in normocobalaminemic dogs (49% vs. 35%; P = .0064). Hyperhomocysteinemia was detected in 53 of 78 (68%) of Greyhounds, being more common in hypo- than in normofolatemic dogs (88% vs. 59%; P = .0175). All healthy Greyhounds, 21 of 30 (70%) of dogs with chronic diarrhea and 6 of 8 (75%) of those with thrombosis, were hyperhomocysteinemic. Serum HCY concentrations were inversely correlated with serum folate concentration (q = -0.28; P = .0386) and were positively associated with serum albumin concentration (q = 0.66; P = .0022). Conclusions and Clinical Relevance: Hyperhomocysteinemia occurs frequently in the Greyhound population. Its association with hypofolatemia suggests decreased intracellular availability of B vitamins, but the functional implications warrant further investigation. Hyperhomocysteinemia in Greyhounds potentially may serve as a spontaneous canine model to further investigate hyperhomocysteinemia in humans.

Une altération du métabolisme de l'homocystéine constitue un facteur de risque pour la survenue des maladies neurodégénératives. Par ailleurs, alors que les effets délétères d'une hypoxie néonatale sévère sont bien connus, il a été récemment montré qu'un épisode hypoxique modéré exerçait une neuroprotection via une stimulation de la neurogenèse. Notre objectif fut l'étude des conséquences cérébrales d'une carence précoce en donneurs de méthyles (folates, vitamine B12) combinée ou non à une stimulation hypoxie modérée. Un modèle in vivo de rats nés de mères carencées en donneurs de méthyles fut utilisé. Il a été étudié les mécanismes impliqués dans un modèle de progéniteurs neuronaux carencés. Les résultats ont montré des atteintes de l'intégrité tissulaire et fonctionnelle de l'hippocampe et du cervelet associée à des déficits comportementaux, à différents stades de la vie chez les animaux carencés malgré le retour à une alimentation standard au sevrage. Ces perturbations sont liées aux processus épigénétiques et à l'homocystéinylation de protéines neuronales. De plus, un dimorphisme sexuel est apparu en lien avec le récepteur nucléaire ER alpha. La neurogenèse issue de l'hypoxie a engendré des conséquences bénéfiques à long terme sur le vieillissement cérébral des rats mâles, avec un maintien de l'intégrité hippocampique. Enfin, la combinaison de la carence et de l'hypoxie, a montré que le conditionnement hypoxique améliorait le devenir tissulaire et fonctionnel du cerveau des animaux carencés. Les mécanismes clés surviendraient au cours de périodes critiques de maturation des différentes structures cérébrales, soulignant l'importance des processus de la programmation foetale / The alteration of homocysteine metabolism has been shown to constitute a risk factor for neurodegenerative diseases. Furthermore, whereas deleterious effects of severe neonatal hypoxia have been well documented, it was shown that a moderate episode of hypoxia can exert a neuroprotection with neurogenesis stimulation. Our main goal was to study the consequences on the brain of an early deficiency of methyl donors (folate, vitamin B12) with or without a hypoxia-related stimulation of neurogenesis. The effects of deficiency were investigated in rats born from dams fed a deficient diet until weaning. In vitro neuroprogenitors were additionally used for the study of cell mechanisms involved. Data showed alterations of tissue integrity in the hippocampus and the cerebellum, with associated behavioural deficits at various ages, despite a return to normal diet at weaning. Brain alterations were shown to be mainly related to epigenetic mechanisms and to homocysteinylation of specific neuronal proteins. Moreover, a sexual dimorphism was depicted, with the participation of ER alpha receptor. Neurogenesis induced in germinative zones by a brief neonatal hypoxia led to long term beneficial effects on brain aging in male rats, with preserved hippocampus integrity, in terms of cell density, synaptic plasticity, and related cognitive functions. Finally, the combination of deficiency and hypoxia revealed that brain conditioning by brief neonatal hypoxia was able to improve tissular and functional brain outcome in deficient rats. The key mechanisms involved would occur at critical periods during the maturation of the various brain structures, thus highlighting the role of fetal programming.

Les carences précoces en donneurs de méthyles (vitamines B9 et B12 notamment) sont à l’origine de malformations congénitales. Elles exercent un effet délétère sur le développement du cerveau et sont associées à une augmentation de l’incidence de pathologies neurologiques et neurodégénératives à l’âge adulte. Un modèle murin de carence en donneurs de méthyles, le modèle MDD, a été développé au laboratoire et a permis d’étudier la réponse à cette carence, et de mettre en évidence des altérations de la structure cérébrale et des défauts de locomotion chez les ratons issus de mères carencées. Ce comportement est contrôlé par le cervelet, dont on sait que le développement est altéré chez les MDD. En revanche, les mécanismes moléculaires mis en jeu dans la réponse à la carence dans le cervelet restent peu compris. Afin d’étudier les gènes et voies de signalisation dérégulés chez les MDD, nous avons réalisé l’étude du transcriptome du cervelet des ratons carencés. Puis, nous nous sommes intéressés aux modifications épigénomiques engendrées par la carence en analysant leur miRnome et les modifications des protéines histones dans leur cervelet. Nous avons mis en évidence des altérations des voies wnt, dans le cervelet des femelles carencées, qui n’ont pas été retrouvées chez les mâles. De même, de nombreux gènes impliqués dans le développement et les fonctions synaptiques sont dérégulés chez les femelles. Nous avons aussi montré des variations de plusieurs marques d’acétylation et de méthylation des histones chez les MDD. Enfin, de manière plus ciblée, nous avons mis en évidence un miARN dont l’expression diminue dans le cervelet des ratons carencés : miR-344-5p. Nos premiers résultats semblent indiquer qu’il est impliqué dans le contrôle de la mort cellulaire. Ces résultats montrent l’implication de dérégulations globales dépendantes du sexe mais aussi des altérations ciblées dans la réponse à la carence. Une amélioration de la compréhension de ces mécanismes moléculaires nous permettra de mieux appréhender le lien qui existe entre carence précoce en donneurs de méthyles, développement cérébral et incidence de pathologies à l’âge adulte / Early methyl-donor deficiencies (e.g. B9 and B12 vitamins) can lead to congenital disabilities. They are behind developmental abnormalities of the brain, and are associated with the development of neurological and neurodegenerative diseases at adulthood as well. In the lab, we developed a methyl donor deficiency rat model called MDD. It has allowed us to show structure alterations of several brain areas and also locomotor coordination impairments in pups born from dams fed a MDD diet. Cerebellum is the brain structure involved in the control of this behavior and we know its development is delayed in MDD. However, the molecular mechanisms underlying methyl donor deficiency still remain misunderstood in this brain structure. In order to study genes and signaling pathways dysregulated in MDD, we performed transcriptomic analysis of deficient pups’ cerebellum. We also led miRnome analyses and histone modifications investigations with the purpose of understanding epigenomic modifications caused by MDD. We showed alterations of wnt signaling pathways in female’s cerebellum which we did not find in males. We also found that several genes involved in cerebellum’s development and synaptic function were dysregulated in females. Regarding epigenomic regulation, acetylation and methylation of histone marks were also modified in females. Finally, we chose miR-344-5p as an interesting candidate to study more specific epigenetic modifications. Its expression is decreased in MDD and it seems to be involved in cellular death control, according to our first results. These results shed light on global dysregulations, in a sex-dependent manner, as a consequence of methyl donor deficiency but also more specific alterations. A better understanding of the molecular mechanisms taking place in response to MDD could help us to link methyl donor deficiency, brain development and neurodegenerative pathologies occurrence at adulthood

Made available in DSpace on 2014-12-17T14:13:32Z (GMT). No. of bitstreams: 1 MarcioLTA_Tese.pdf: 1453040 bytes, checksum: 7c0ed7c44a56eb54d2170012eedbfa04 (MD5) Previous issue date: 2009-11-27 / The imprecision of the frontier that separates those cognitive deficits inherent to the human physiological aging process from those which represent the early signs of nervous system degenerative pathologies ,very prevalent among the elderly, has brought attention to the need of studies aiming to establish clinical and/or laboratorial criteria to allow this differentiation. Elderly people living in poor and developing countries are frequently exposed to precarious socioeconomic conditions which facilitate the development of an array of pathologies which have metabolic and nutritional dysfunctions as the established or proposed etiological agents. The levels of certain micronutrients, such as the vitamins B12 and B9 (folic acid), and of some intermediary metabolites, such as homocysteine are being thought of as etiological factors and/or as biological markers of a group of alterations which affect the normal functioning of the nervous system with important reflexes upon cognitive performance. This study aims to investigate the influence of homocysteine, B12 vitamin and folic acid levels on the cognitive performance of the low income elderly population. This transversal study took place in Natal, Rio Grande do Norte State, Brazil, and involved 205 dwelling elderly people, users of the Programa de Sa?de da Fam?lia, a public healthcare program, maintained by the city s health authorities. A multidimensional questionnaire was used to assess the socio-demographic aspects and the overall health and nutrition conditions. The cognitive performance was measured by the use of the Portuguese version of the Mini Mental State Exam (MMSE). The serum levels of homocysteine, B12 vitamin and folic acid were determined by chemiluminescence. The association between the socio-demographic and serum levels of Hcy, B12 vitamin and folic acid was determined by multiple linear regression. Serum levels higher than 13.5 &#956;mol/l, indicative of hyperhomocysteinemia (HHcy), were found on 25.4% of the sample, being more prevalent in men (p<0.05). Deficitary levels of folic acid (<5ng/mol) and of B12 vitamin (<193 pg/ml) were found on 3.9% and 10.2% of the sample respectively. A negative correlation was found between cognitive performance with both age and HHcy and a positive correlation was found between cognitive performance and schooling. The isolated HHcy R2 values were an explanation to only 4% of the variance of the MMSE scores. However, when associated with schooling and age, this model explains about 25% of this association / A imprecis?o da fronteira que separa os d?ficits pr?prios do processo de envelhecimento fisiol?gico humano daqueles que representam os sinais precoces das patologias degenerativas de grande preval?ncia entre idosos, tem chamado a aten??o para a necessidade da produ??o de estudos voltados para o estabelecimento crit?rios cl?nicos e/ou laboratoriais que permitam essa diferencia??o. Idosos de popula??es de pa?ses pobres e/ou em desenvolvimento s?o freq?entemente expostos a condi??es socioecon?micas prec?rias prop?cias ao desenvolvimento de um conjunto de patologias, disfun??es metab?licas e nutricionais. Os n?veis de determinados micronutrientes e de alguns metab?litos intermedi?rios v?m sendo vistos como fatores etiol?gicos e como marcadores biol?gicos de um conjunto de altera??es que afetam a fun??o normal do sistema nervoso com reflexos importantes sobre o desempenho cognitivo. N?veis elevados de homociste?na (Hcy) e d?ficits nutricionais e /ou metab?licos da vitamina B12 e B9 (?cido f?lico) t?m sido apontados como preditores e/ou como fatores etiol?gicos de altera??es cognitivas. O objetivo desse estudo foi avaliar a influ?ncia dos n?veis de homociste?na, Vitamina B12 e ?cido f?lico no desempenho cognitivo de idosos de baixa renda. Este estudo transversal desenvolvido em Natal, Rio Grande do Norte, Brasil, incluiu 205 idosos n?o institucionalizados atendidos pelo Programa de Sa?de da Fam?lia da Secretaria Municipal de Sa?de do munic?pio. Um question?rio multidimensional foi utilizado para avaliar os aspectos sociodemogr?ficos e as condi??es gerais de sa?de e nutri??o. O desempenho cognitivo foi aferido utilizando-se a vers?o em portugu?s do Mini-Exame do Estado Mental (MEEM). Os n?veis s?ricos de homociste?na, Vitamina B12 e ?cido f?lico foram determinados por quimioluminesc?ncia. A associa??o entre as vari?veis sociodemogr?ficas e os n?veis s?ricos de Hcy Vitamina B12 e ?cido f?lico foi determinada atrav?s de regress?o linear m?ltipla. Valores s?ricos acima de 13,5 &#956;mol/l indicativos de hiperhomocisteinemia (HHcy) foram encontrados em 25,4% da amostra sendo mais prevalente em homens (p<0,05). N?veis deficit?rios de ?cido f?lico (<5ng/ml) e de Vitamina B12 (<193 pg/ml) foram encontrados em 3,9% e 10,2% dos indiv?duos respectivamente. O desempenho cognitivo mostrou uma correla??o negativa com a idade e a HHcy e positiva com a escolaridade. Os valores R2 da HHcy isolada explicaram apenas 4% da vari?ncia da pontua??o do MEEM. Contudo, quando associada escolaridade e idade, este modelo explica aproximadamente 25% desta associa??o.